To determine whether timed administration of aspirin ameliorates the effects of celecoxib on blood pressure.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used and effective treatment of inflammatory pain. However, all NSAID have the potential to raise blood pressure (BP), cause the development of new hypertension or exacerbate preexisting hypertension. Strategies to mitigating that risk short of withholding the analgesic are missing. In this proposal, the investigators wish to determine whether timed administration of low dose aspirin can be developed as a low cost intervention with well-defined risk profile to mitigate the blood pressure raise associated with the COX-2 selective NSAID celecoxib. Low dose aspirin administered in the evening, but not in the morning, normalizes the mean arterial BP in clinical studies of prehypertension, mild essential hypertension and preeclampsia. The investigators will address this in an interventional study in healthy volunteers who displayed a blood pressure increase during celecoxib treatment in an ongoing study. Since individuals have varying chronotypes and work/social rhythms, parameter measuring day/night patterns, the chronobiome, will be part of this study.

Inclusion Criteria:

1. Men and women greater than 18 years of age

2. Subjects must be in good health based on medical history, physical examination, vital signs, and laboratory tests. In order to ensure sufficient enrollment of subjects in the higher age groups, volunteers with the following conditions may participate in the study:

   1. Adequately controlled hypertension, with diastolic blood pressure ≤100 mmHg at screening.
   2. Total cholesterol of ≤270 mg/dL

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

4. Has not used tobacco products, including smoking cessation nicotine-containing products (e.g., nicotine patch, nicotine gum), for at least the 3 months prior to screening.

5. Female subjects of child bearing potential must be using a medically acceptable method of contraception (oral contraception, Depo-Provera injection, IUD, condom with spermicide, diaphragm, cervical cap, progestin implant, abstinence, tubal ligation, oophorectomy, TAH) throughout the entire study period. All female subjects must consent to a serum and urine pregnancy test at screening and close-out and a urine pregnancy test just prior to the start of each treatment phase of the study, which must be negative at all time points.

6. All subjects must consent to a urine drug and nicotine test at screening. Results must be negative. A positive result will be reported to the subject.

7. Does not consume more than 1 alcoholic beverage per day on average.

8. Able and willing to refrain from alcohol use within 48 hours prior to the first dose of study drug and during the study period until the final study visit.

9. Able to understand and comply with study procedures.

10. Able and willing to provide written informed consent prior to any study procedures being performed.

Exclusion Criteria:

1. Female subjects who are pregnant or nursing a child.

2. Subjects who have received an investigational drug or used an experimental medical device within 30 days prior to screening, or who gave a blood donation of ≥ one pint within 8 weeks prior to screening.

3. Subjects with any coagulation, bleeding or blood disorders.

4. Subjects who are sensitive or allergic to celecoxib (Celebrex) or aspirin or their components.

5. Subjects who are sensitive or allergic to aspirin or other NSAIDs.

6. Subjects with documented history of any gastrointestinal disorders, including bleeding ulcers.

7. History of significant cardiovascular disease (including stroke or TIA), renal, hepatic, respiratory (except infections which longer > 6 months prior to screening), immune, endocrine, hematopoietic disorder or neurological disorders.

8. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell cancer resolved by excision, or carcinoma in situ of the cervix adequately treated).

9. Has taken any prescription medication other than hormone replacement therapy (including males taking testosterone as a hormone replacement to treat a documented low testosterone level), thyroid replacement hormones, anti-hyperlipidemic agents, or anti-hypertensive medications. Individuals taking other/additional chronic stable medications can be considered on a case-by-case basis for inclusion in the study if agreed upon by judgment of the investigators.

10. Has taken the following NSAID or antisecretory agents within 2 weeks prior to study drug administration:

    1. Nonsteroidal anti-inflammatory drugs (NSAIDs) including acetaminophen or other medications for pain, including aspirin or aspirin-containing products
    2. Proton pump inhibitors, including Prilosec®, Prevacid®, Aciphex®, Protonix®, or Nexium® (antacid medications, including OTC products, are not permitted within 24 hours of dosing)
    3. H2 blockers, including Tagamet®, Zantac®, Axid®, or Pepcid®

11. Has ever taken the following anti-platelet or anti-coagulant agents:

    1. Any anti-platelet agent, including Aggrenox®, Brilinta®, Plavix®, Ticlid®, Pletal®, ReoPro®, Integrilin®, Aggrastat®, Persantine®, or Effient®
    2. Any anti-coagulant including Arixtra®, Coumadin®, acenocoumarol, Lovenox®, phenprocoumon, phenindione, heparin, Exanta®, Pradaxa®, argatroban, lepirudin, hirudin, bivalirudin, or Xarelto®

12. Used dietary or herbal supplements containing salicylates, Vitamin E, fish oil, or any other herbal supplements, within 14 days of study drug administration.

13. Subjects with any abnormal laboratory value or physical finding that according to the investigator may interfere with interpretation of the study results, be indicative of an underlying disease state, or compromise the safety of a potential subject.

14. Subjects who have had a history of drug or alcohol abuse within the last 6 months.

15. Subjects who are unwilling to provide a blood sample for genetic analyses and creation of a lymphoblastoid cell line.

16. Any contraindication listed below in the separate paragraph "Contraindications for the use of CorTemp® Disposable Temperature Sensors".

17. Volunteers enrolled in the sub-study who do not own a smartphone.

to be determined

Administration of acetylsalicylic acid versus placebo will be masked