Effects of Dual Cyclooxygenase-2 and Carbonic Anhydrase Inhibition

Inclusion Criteria: 1. Age 18-60 years old, able and willing to provide written informed consent to participate in the study; 2. Subjects must be in generally good health as determined by pre-study medical history, physical examination, clinical laboratory tests and 12-lead electrocardiogram (ECG); 3. Body mass index (BMI) 19-32 kg/m2; 4. Normal blood pressure (BP) \[systolic BP 90-140 mmHg, diastolic BP 50-90 mmHg\] and heart rate (HR) \[resting HR 45-90 bpm\] without medication; 5. Clinical chemistry profile including electrolytes, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), creatinine, and urea must be within the normal range without medication; screening liver enzymes may be up to 1.5x normal range; screening CPK must be within 2x normal range without medication; 6. Urinalysis including urinary creatinine must be within normal limits (trace findings and minor deviations are acceptable per the clinical decision of the Principal Investigator); 7. Subjects must be non-smokers and non-drinkers or willing to abstain from smoking, alcohol, caffeine and high-fat foods for the duration of study; 8. Subjects must be able to read, understand and follow the study instructions; 9. Subjects and their sexual partners must agree to use double barrier contraception during the study period and for 2 months afterward or provide proof of surgical sterility. Double barrier contraception may include, but is not limited to, using a male condom with spermicide; having a female sexual partner who agrees to use an IUD with spermicide, a female condom with spermicide, a diaphragm with spermicide, a cervical cap with spermicide; or having a sterile sexual partner. Female subjects must be non-pregnant, non-lactating, and either postmenopausal for at least 1 year, surgically sterile for at least 3 months, or willing to use double barrier contraception from 28 days prior to study enrollment and/or their last confirmed menstrual period (whichever is longer) until 2 months after final clinic visit. For all females, the pregnancy test result must be negative at Screening; 10. Subjects must tolerate the insertion of an intravenous line of the size ≥ 20 gauge for the drug administration study days. Exclusion Criteria: 1. Use of any non-study medication(s) including low dose aspirin for cardiovascular prophylaxis within 2 weeks prior and 2 weeks after receipt of each dose of study drug; 2. Use of chemotherapy agents or history of cancer, other than non-metastatic skin cancer that has been completely excised, within five (5) years prior to the screening visit; 3. History of bacterial or viral infection requiring treatment with antibiotics or antivirals within 3 months of study; 4. Presence or history of peripheral edema within the past 5 years; 5. History of congestive heart failure; 6. Use of drugs which are P450 3A4 inducers or inhibitors within the past 30 days (e.g. alprazolam, chlorpheniramine, cimetidine, fluoxetine, haloperidol, ketoconazole, itraconazole, erythromycin, clarithromycin, sildenafil, simvastatin, St. John's Wort); 7. Use of prescribed systemic or topical medications or any dietary aids or foods that are known to modulate drug metabolizing enzymes (e.g. grapefruit juice) within 14 days of dose administration; 8. Difficulty in swallowing oral medications; 9. History of seizure disorder; 10. Serious psychosocial co-morbidities; 11. Cognitive or psychiatric disorders, or any other condition that could interfere with compliance with study procedures and/or confinement in a clinical study unit for 2 days or longer; 12. History of drug or alcohol abuse within one year prior to screening; 13. Use of any other investigational drug within 1 month prior to enrollment; 14. Use of any prescription drugs within 1 month prior to enrollment; 15. Use of over the counter medication excluding routine vitamins, but including mega-dose vitamin therapy, within one week of enrollment; 16. Donation and/or receipt of any blood or blood products within 3 months prior to enrollment; 17. Active gastrointestinal, renal, hepatic, or coagulant disorder within 1 month prior to enrollment; 18. Esophageal or gastroduodenal ulceration within 1 month prior to enrollment; 19. Hypersensitivity to NSAIDs, sulfonamides, COX-2 inhibitors, or carbonic anhydrase inhibitors; 20. Known allergy or hypersensitivity to sulfa drugs; 21. Family history of significant cardiac disease (i.e. sudden death in first degree relative; myocardial infarction prior to 50 years old); 22. Occult blood in stool (fecal occult blood test).