Variability in Response to Non-steroidal Anti-inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of
inflammatory pain. Pain is a highly subjective experience, and selecting an analgesic regimen
that provides optimal pain relief for a specific patient can be challenging. Moreover,
patients often express a preference for a particular NSAID, raising the possibility that the
efficacy in relieving pain is variable among individuals. However this has never been studied
systematically. The clinical decision-making process has been further complicated by the
recognition that NSAIDs cause serious thrombotic adverse events in some patients (1).
Elucidating the factors that influence an individual patient's risk of cardiovascular
complications and the likelihood of analgesic efficacy will enable clinicians to prescribe
NSAIDs rationally in order to maximize their therapeutic benefit while minimizing the risk of
adverse cardiovascular events.

NSAIDs are a chemically diverse class of therapeutic agents that exert their analgesic and
anti-inflammatory effects via inhibition of cyclooxygenase (COX)-1 and/or COX-2, enzymes that
catalyze the first committed step in prostaglandin (PG) synthesis. PGs produce a diverse
array of biologic effects via activation of prostanoid receptors, and play important roles in
a variety of pathologic and homeostatic processes (2). COX-2 is readily induced in response
to pro-inflammatory stimuli and has been considered the primary source of inflammatory PGs.
In contrast, the production of PGs with homeostatic functions, such as gastric epithelium
cytoprotection, has been ascribed to COX-1, which is constitutively expressed in most tissues
(2). Consequently, COX-2-selective NSAIDs, including rofecoxib, valdecoxib, and celecoxib,
were developed in order to retain the anti-inflammatory and analgesic effects of inhibition
of COX-2-derived PG formation, while avoiding the gastrointestinal toxicity of traditional
NSAIDs (i.e. aspirin, ibuprofen, naproxen, etc) that inhibit both isoforms. Although fewer
gastrointestinal complications were observed in clinical trials, treatment with
COX-2-selective NSAIDs increased the risk of serious cardiovascular adverse events, including
myocardial infarction, stroke, and heart failure (1,3).

The risk of thrombotic events associated with the use of NSAIDs, particularly those selective
for COX-2, is mediated via suppression of COX-2-derived prostacyclin formation in endothelial
and vascular smooth muscle cells (4,5). Prostacyclin possesses potent anti-thrombotic and
vasodilatory effects, and thus acts as a general inhibitor of platelet activation in vivo
(2). Traditional NSAIDs also inhibit COX-2 in the vasculature, but the associated risk of
thrombosis is mitigated to some extent by inhibition of formation of thromboxane A2 (TxA2), a
COX-1-derived PG released by activated platelets that promotes platelet activation and
aggregation (1,3). Thus, the risk of thrombosis for a particular NSAID is dependent upon its
relative selectivity for COX-2 over COX-1 (3,6). In addition to their effects on vascular PG
production, all NSAIDs inhibit renal PG formation, resulting in sodium retention and
hypertension, which may further augment cardiovascular risk (1,3,7).

Currently, it is recommended that NSAIDs be avoided or used only for a limited duration in
patients classified as high cardiovascular risk (8). These recommendations are supported by
studies demonstrating that even short-term NSAID use increased the incidence of
cardiovascular events in patients undergoing coronary artery bypass grafting (9,10) and
following a myocardial infarction (11,12). However, long-term treatment with COX-2-selective
NSAIDs also increased the incidence of cardiovascular events in patients considered to be at
low baseline risk (13,14), consistent with risk transformation due to atherogenesis and
indicating traditional cardiovascular risk factors alone are not sufficient to guide
therapeutic decisions. Thus, additional studies are necessary to define comprehensively the
factors that modify the cardiovascular risk of NSAID use and facilitate the progressive
personalization of NSAID therapy.

Inclusion Criteria:

- Adult men and women greater than 18 years of age who are non-smokers and in good
health based on medical history, physical examination, vital signs, and laboratory
tests. Volunteers with adequately controlled hypertension and hyperlipidemia (total
cholesterol of ≤270 mg/dL) may participate in the study.

Exclusion Criteria:

- Female subjects who are pregnant or nursing a child.

- 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.

- Subjects with any coagulation, bleeding or blood disorders.

- Subjects who are sensitive or allergic to celecoxib (Celebrex) or naproxen (Naprosyn)
or their components.

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

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

- 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.

- 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).

- 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.

- Has taken NSAIDs or anti-secretory agents (proton pump inhibitors or H2 receptor
antagonists) within 14 days prior to study drug administration

- Has ever taken the any anti-platelet or anti-coagulant agents

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

- 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.

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

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