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PHARMACODYNAMICS |
From Merck Research Laboratories, Rahway, New Jersey (Dr Schwartz, Dr Thach, Ms Miller, Mr Hreniuk, Ms Hilliard, Ms Snyder, Dr Gertz, Dr Gottesdiener) and Clinical Pharmacology Associates, Miami, Florida (Dr Lasseter).
Address for correspondence: Dr Jules I. Schwartz, Merck Research Laboratories, 126 E. Lincoln Avenue, PO Box 2000, RY34-A552, Rahway, NJ 07065-0900; e-mail: jules_schwartz{at}merck.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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. Decreases were greater for both metabolites following naproxen. Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with moderately greater increases for etoricoxib relative to other active treatments on day 14. Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen but not for celecoxib.
Key Words: Etoricoxib • celecoxib • naproxen • sodium excretion • blood pressure
In studies of renal physiology and in clinical settings, the cyclooxygenase-2 (COX-2) selective NSAIDs—celecoxib, rofecoxib,* and valdecoxib—have demonstrated effects on renal function similar to those of traditional NSAIDs.1-3 Minor dose-dependent changes were noted in urinary PG excretion, GFR, and sodium retention in the presence of sodium restriction or intravascular volume depletion.4,5 Increases in blood pressure (BP), attenuation of antihypertensive effects, and acute renal failure, similar to those reported for traditional NSAIDs, have been observed in clinical trials with COX-2-selective NSAIDs.2,6-11
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The present study evaluated and compared the effects of oral etoricoxib 90 mg once daily, oral celecoxib 200 mg twice daily, oral naproxen 500 mg twice daily, or placebo on sodium excretion, creatinine clearance, body weight, and BP in subjects 60 to 85 years of age consuming a diet supplying a fixed amount of sodium, 200 mEq per day, which is typical of a Western diet commonly consumed in the absence of restrictions on sodium intake.13 The dosages of etoricoxib and celecoxib represent the maximum dosages approved for the chronic treatment of the signs and symptoms of rheumatoid arthritis.14,15 The dosage of naproxen is the maximum indicated for long-term treatment of osteoarthritis and rheumatoid arthritis.16
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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34 kg/m2 and with creatinine clearances 
40 mL/min, as estimated using serum creatinine concentrations.17 All were in good general health on the basis of medical histories, physical examinations, and routine laboratory tests. Subjects were excluded from participating in the study if they had any clinically significant past or present medical conditions or any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering study drugs to the subject. Concomitant therapeutics that were not permitted were any medications containing NSAIDs or inducers or inhibitors of drug-metabolizing enzymes.
Study Design
A double-blind, randomized, placebo-controlled, double-dummy, parallel-group study (sponsor protocol number 053) was conducted at 2 sites in the United States from June 5, 2001, to March 7, 2002. The protocol and patient consent procedures were approved by the Independent Investigational Review Board (Plantation, Florida) and the Southern Institutional Review Board (Miami, Florida). All patients provided written informed consent before participating in the study.
Subjects entered the clinical research units as inpatients to begin a run-in period to establish steady-state sodium balance prior to the first day of dosing (Figure 1). Starting on the day of admission (designated day R1), subjects were placed on an isocaloric diet that provided 200 mEq sodium, 80 to 120 mEq potassium, and approximately 0.8 g protein/kg for at least 8 days (days R1-R7 and day -1) before the start of treatment. Throughout the run-in period to establish sodium balance and the 15-day treatment period, patients remained in the clinical research units and consumed only the isocaloric diet provided by the clinical research unit. No food or beverages, other than those provided by the clinical research unit (eg, distilled or sodium-free water), were permitted during the study. Meals were consumed in their entirety.
Throughout both the dosing and evaluation periods (days 1-15), subjects continued as inpatients in the clinical research units for daily 24-hour urine collections and routine clinical measurements. Sodium balance was considered to have been achieved in the run-in period once the subject was stable in weight (within 0.5 kg on 2 successive mornings beginning on or after day R6, or starting after the sixth day on the metabolic diet) and had urinary sodium excretion within 180 to 220 mEq/24 hours. Subjects meeting these requirements began day -1 activities. For subjects who met the inclusion criteria, it was unlikely that urinary sodium excretion at day -1 would be much lower than 180 mEq or much greater than 220 mEq, although the day -1 sodium excretion value was not known until after the first dose of study drug had been administered. In the event that the sodium excretion value for day -1 was later found to be outside the range of 130 to 270 mEq, the subject was not included in the per protocol analysis of urinary sodium excretion, body weight, creatinine clearance, and urinary potassium excretion. Subjects who did not achieve sodium balance by day R7 could continue for up to 5 additional days until balance was achieved. Subjects who failed to achieve balance after that time were discontinued from the study.
Treatment Regimens
As subjects achieved sodium and weight balance, they were sequentially assigned to an allocation number. The treatment associated with the allocation number was randomly assigned by a computer program prior to the study. The treatment groups for the study were etoricoxib (90-mg tablet once daily), celecoxib (200-mg capsule twice daily), naproxen (500-mg tablet twice daily), or matching placebos. The active treatment continued for 14 days and included the morning dose on day 15. Matching placebo capsules or tablets were provided for each active treatment, so that each subject took a total of 2 tablets and 1 capsule at 
8 AM and 1 tablet and 1 capsule at 8 PM each day, to maintain the double-blind nature of the study.
Urinary Measurements
Twenty-four-hour urine collections commenced on day R6 and continued to the end of the study. The starting time for collection of urine was 8 AM, and the final collection was a void just prior to 8 AM on the next day. Urinary sodium and potassium excretion was measured for each 24-hour period for the duration of the study. The baseline evaluation criterion for sodium excretion was the average of the 3 days prior to drug administration. This included the day -1 value and the values for the 2 previous days.
Urinary creatinine was determined for each 24-hour period starting on day R5 and continuing until the subject was eligible for the study. The average GFR during the 3 days prior to drug administration served as the baseline value. Glomerular filtration rates for day 7 and day 15 were used to determine treatment effects.
The urinary excretion of the stable metabolites of thromboxane, 11-dehydrothromboxane B2 (TX-M), and prostacyclin, 2,3-dinor-6-keto PGF1 (PGI-M) was quantified during corresponding 8-hour collection periods on day R5 (baseline) and on day 15 during treatment.
Analyses of TX-M and PGI-M were performed separately using gas chromatography/tandem mass spectrometry (GC/MS/MS) methods with stable isotope derivatives of the analytes as internal standards. For TX-M, internal standard, 11-dehydro TXB2-d4, containing 4 deuterium atoms at the 3, 3,' 4, and 4' positions was added to thawed urine samples, which were then activated by acidification and incubated at 37°C for 4 hours to ensure that only the lactone form was present. Samples were partially purified with solid-phase extraction columns and then underwent a second acid activation and derivatization by pentafluorobenzyl bromide esterification of the acid moiety and trimethylsilylation of the alcohols before analysis by GC/MS/MS in negative chemical ionization mode. The daughter ions of TX-M and TXB2-d4 (daughter ions = 243 and 247 m/z, respectively; parent ions = 511 and 515 m/z, respectively) were monitored to produce a signal with minimal background interference. The lower limit of reliable quantitation (LLORQ) (20% interassay coefficient of variation) was 39.6 pg/mL. Within- and between-day reproducibility, expressed as coefficient of variation percent (CV%), was 3% to 5% and 10% to 14%, respectively, across the range of standard concentrations.
For analysis of PGI-M, internal standard, 2,3-dinor-6-keto-prostaglandin F1-20, 20, 20-d3, was added to aliquots of urine samples, which then underwent an alkali treatment prior to affinity extraction using a PGI-M antibody bound to agarose beads. The samples then underwent 3 separate derivatization steps (methyloximation of the keto group using methoxyamine hydrochloride, followed by C18 solid-phase cleanup, esterification with pentylfluorobenzyl bromide, and then trimethylsilylation) before analysis by GC/MS/MS in negative chemical ionization mode. The daughter ions of PGI-M and d3-PGI-M (daughter ions = 239.5 and 242.5, respectively; parent ions = 587 and 589 m/z, respectively) were monitored to produce a signal with minimal background interference. The LLORQ was 8.5 pg/mL. Within- and between-day reproducibility (CV%) was 2.5% to 8% and 7% to 14%, respectively, across the range of standard concentrations.
Serum Electrolytes
Whole-blood samples were collected from each subject, after a midnight to 8 AM fast when only water was permitted and before any other activities, for determinations of serum levels of sodium, potassium, chloride, bicarbonate, and creatinine before the start of the study; on days R6 and R7 (and additional days during the period of sodium stabilization, if necessary); and on days 1, 2, 3, 4, 8, 14, and 15.
Body Weight
Subjects were weighed daily on a balance beam scale that was calibrated weekly. Time of day, scale, and the person performing the measurement were the same throughout the study. The body weight on day 1 prior to the first dose was the baseline value for the study.
Blood Pressure Assessments
Ambulatory BP (systolic [SBP] and diastolic [DBP]) was measured with an ambulatory BP monitor (Model 90207, SpaceLabs Medical, Inc, Issaquah, Washington). Ambulatory BP was measured over a 24-hour period at 15-minute intervals during awake time on the dominant arm beginning at approximately 8 AM on scheduled days, immediately following the BP measurement by manual mercury sphygmo-manometry. The measurement interval was every 20 minutes during the sleeping hours. The baseline values were those determined on day -1.
Manual BP was determined at 8 AM and 8 PM after the subject had been sitting for 10 minutes and at least 10 minutes after any blood draws. The average of 3 replicate measurements for SBP and DBP obtained at 1 to 2 minutes apart was recorded. The baseline values were those determined on day -1.
Safety and Tolerability Assessments
Clinical safety and tolerability were based on findings of physical examinations, electrocardiograms, clinical laboratory test results, and collection of adverse experiences (AEs) throughout the study. Drug-related AEs were those determined by the investigator to be possibly, probably, or definitely drug related.
Statistical Analyses
Between-treatment differences in least squares (LS) mean change from baseline and 90% confidence intervals (CIs) for the differences were calculated using an analysis of covariance (ANCOVA) model. The final ANCOVA model included terms for baseline, treatment, and study site. Interactions of treatment with study site and treatment by baseline were assessed but not included in the final model because they were not statistically significant (P < .05) or not clinically meaningful. Results for the Shapiro-Wilks test for normality and Levene's test for homogeneity of variance did not suggest any departure from the assumption of the ANCOVA model for most analyses. If normality was not established, an ANCOVA based on nonparametric procedures was employed. Unless stated otherwise, the results from the nonparametric between-treatment comparisons were similar to the parametric results, resulting in the same conclusion.
The primary endpoint was the LS mean change from baseline in the average 24-hour urinary sodium excretion during the first 72 hours of treatment between etoricoxib and celecoxib. Power calculations were based on previous experience with studies with similar goals and similar design.4,10 Assuming 20 subjects per group completing the study, there was a 95% probability that during the first 72 hours, the 90% CI for the difference in mean reduction from baseline in daily average urinary sodium excretion between etoricoxib and celecoxib would fall within ±30 mEq if the true difference was zero. Differences less than ±30 mEq would not be considered clinically meaningful.
Secondary endpoints included LS mean changes for all treatments from baseline in urinary sodium excretion during the first 72 hours and weeks 1 and 2 of treatment, average ambulatory BP over 24 hours, body weight on day 14, creatinine clearance at days 7 and 14, and serum electrolytes at day 14. The percentage changes in urinary prostanoids from baseline (day R4) on day 15 were also analyzed. All percent change calculations were computed on log-transformed data and then back-transformed to the percent inhibition scale. The back transformation of the between-treatment mean differences from the log scale and corresponding 90% CIs were computed using previously described methods.18 Differences between values were considered significant when P .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Urinary Sodium Excretion
All active treatment groups had significantly larger decreases in urinary sodium excretion from baseline during the first 72 hours of treatment relative to the placebo group (Figure 2). Etoricoxib and celecoxib were not statistically different with respect to the change in daily urinary sodium excretion during the first 72 hours of treatment and during the first and second weeks of treatment (Table II). Even though the reduction from baseline was statistically significantly greater for naproxen when compared with placebo during the first 72 hours of treatment (P = .005), the lower limit of the 90% CI (-28.1 mEq/24 h) was less than the predefined value of ± 30 mEq over a 24-hour period for a clinically significant difference and was therefore considered not to be clinically meaningful. During the first 72 hours of treatment, both etoricoxib and celecoxib produced a statistically significant reduction of sodium excretion versus placebo (P < .001). Changes caused by both of these agents were considered clinically meaningful because the lower limit of the 90% CIs exceeded the predefined range of ±30 mEq over a 24-hour period.
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The reductions in urinary sodium excretion returned toward baseline within approximately 4 days in all treatment groups (Figure 2). When averaged over the first week of treatment (a secondary endpoint), all active treatment groups were significantly lower than their corresponding baseline, and all except naproxen had significantly greater reductions in average daily urinary sodium excretion compared with the placebo group (Table II). When averaged over the entire 2-week treatment period (a secondary endpoint), there were no significant differences between any treatment group and placebo, although all groups remained at significantly greater sodium retention levels with respect to their baseline levels (Table II).
Urinary Potassium Excretion
At day 14, the LS mean changes (SD) from baseline in urinary potassium excretion were -3.2 (7.6), -1.4 (6.4), -0.3 (6.4), and 2.0 (6.4) mEq/L for placebo, etoricoxib, celecoxib, and naproxen, respectively. Only naproxen demonstrated a significant difference compared with placebo (P = .035). Considering the direction of the change, it does not appear to be clinically meaningful.
Creatinine Clearance
At day 7 of treatment, the LS mean changes (SD) from baseline in creatinine clearance were not significantly different among treatment groups (-1.5 (8.0), -4.0 (6.4), 0.1 (6.4), and -3.1 (6.4) mL/min for placebo, etoricoxib, celecoxib, and naproxen, respectively). At day 14 of treatment, the LS mean changes (SD) from baseline in creatinine clearance were -4.7 (11.6), -5.8 (11.5), 4.4 (11.5), and 2.0 (11.5) mL/min for placebo, etoricoxib, celecoxib, and naproxen, respectively. The differences at day 14 between etoricoxib and celecoxib (P = .006) and etoricoxib and naproxen (P = .033) were significant, but given the similarity between etoricoxib and placebo and the direction of the changes for celecoxib and naproxen, these difference were not considered clinically meaningful.
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Urinary Prostanoids
At baseline, the urinary prostanoid metabolites excreted during the 8-hour sampling from the run-in period averaged 823 pg/mg creatinine for the thromboxane metabolite TX-M and 119 pg/mg creatinine for the prostacyclin metabolite PGI-M (Table I). Naproxen was the only active treatment associated with a statistically significant LS mean percent change (SD) from baseline of -84.5% (6.0) versus placebo for TX-M at day 15 (Figure 3). The LS mean percent changes (SD) in urinary PGI-M from baseline were not different between etoricoxib (-57.9% (18.8)) and celecoxib (-57.2% (19.3)), but both were significantly different from placebo (P < .001; Figure 3). For naproxen, the LS mean change (SD) from baseline was -76.2% (10.5), which was significantly (P < .001) different from all other treatment groups (Figure 3).
Serum Electrolytes
No significant between-treatment group differences were observed for LS mean changes from baseline for serum sodium, potassium, chloride, or bicarbonate at day 14. When compared with placebo, only a small increase (1.6%) in serum chloride with etoricoxib reached the level of a significant difference (P = .013).
Blood Pressure Measurements
The changes in ambulatory BP over the 24-hour period on day 14 to day 15 are presented in Figure 4. The between-treatment differences in LS mean change from baseline in SBP were significantly (P < .05) different for the active treatments relative to placebo (Table III). The increase in SBP with etoricoxib was also significantly (P < .05) greater than the increase with celecoxib or naproxen (Table III). These results were consistent with those obtained with manual SBP at 8 AM on day 14 (Table III).
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For ambulatory average 24-hour DBP, the LS mean changes from baseline for day 14 are presented in Table III and Figure 4B. Only the LS mean increase from baseline for etoricoxib was significantly different. The LS mean increases for naproxen and etoricoxib compared with placebo were significantly different. For ambulatory DBP, there were no significant differences among active treatments. These results were consistent with those obtained with manual DBP obtained at 8 AM on day 14 (Table III).
Safety and Tolerance
All treatments were generally well tolerated during the study. A total of 14 (16%) subjects had at least 1 clinical AE after the start of treatment, including 4 treated with placebo, 2 with etoricoxib, 2 with celecoxib, and 6 with naproxen. For 10 of these subjects (3 placebo, 2 etoricoxib, 1 celecoxib, and 4 naproxen), the AE was noted as mild and considered by the investigator to be possibly related to the drug; these were primarily diarrhea, constipation, and headache. Three other subjects had AEs that the investigator considered mild and not related to treatment. No laboratory AEs were identified. No subject discontinued because of an AE.
One subject (a 72-year-old woman in the celecoxib group) experienced atrial fibrillation at the poststudy visit, which was 10 days after completing the treatment phase of the study. This adverse experience was rated by the investigator as serious but probably unrelated to study drug. The subject recovered fully after appropriate treatment at a local hospital.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Using the same criterion for the secondary endpoints, urinary sodium excretion over 1 and 2 weeks of treatment, etoricoxib 90 mg and celecoxib 200 mg bid did not meaningfully differ from each other or with naproxen 500 mg bid. A similar lack of differences between treatment groups was observed for the related parameter, change in body weight, over the 2 weeks of treatment.
After the initial reduction in urinary sodium excretion at day 1, excretion subsequently returned toward baseline levels. This change suggests that urinary sodium excretion pathways were reset after 24 hours, denoted by the increase in sodium excretion, which may represent up-regulation of COX enzymes or other renal homeostatic mechanisms coming into play.20-22
Although ambulatory SBP (a secondary endpoint) was modestly increased from baseline on day 14 for all active treatments, the increase was moderately higher for etoricoxib compared with the other active treatments. The observations for the manual SBP and DBP on day 14 were in the same rank order as that seen with the ambulatory method.
Even in a rigorously controlled study such as ours, the observed effects of treatment on blood pressure may be variable and difficult to reproduce. It is necessary to recognize that etoricoxib's effects on blood pressure could be different from the comparators in this study. Data from the MEDAL (Multinational Etoricoxib vs Diclofenac Arthritis Long Term) program23 currently provide the largest comparison of etoricoxib's effects on blood pressure compared with a traditional NSAID (ie, diclofenac). The MEDAL program enrolled more than 34 000 arthritis patients treated with etoricoxib 60 or 90 mg, or diclofenac 150 mg daily. Mean duration of exposure was 18 months. Clinically important increases in renal function endpoints (eg, fluid retention and blood pressure) were observed with etoricoxib compared with diclofenac. Specifically, the incidence of confirmed congestive heart failure (etoricoxib 90 mg) and discontinuations due to hypertension (etoricoxib 60 and 90 mg) were higher with etoricoxib. Elevated blood pressure is a risk factor for cardiovascular events and should be carefully monitored in patients receiving chronic therapy with any NSAID. In the MEDAL program, patients with hypertension at baseline experienced higher rates of confirmed thrombotic cardiovascular events compared with those patients who did not. However, there was no difference in the rates of confirmed thrombotic cardiovascular events between the etoricoxib and diclofenac treatment groups, regardless of baseline risk factor status.
In healthy individuals with adequate hydration, as included in the present study, PGs do not play a crucial role in the maintenance of water and sodium homeostasis; however, when renal perfusion is diminished, renal PGs are important for compensatory regulation of this function.1,24 No individuals with cardiovascular disease or diminished renal function were included in this study.
The most important renal PGs are PGI2 (prostacyclin), which increases potassium secretion and is a potent vasodilator, and PGE2, which helps to control sodium reabsorption. Measurement of urinary PGI-M excretion has become a routinely used indicator of systemic PGI2 production.10,25,26 In this study, etoricoxib 90 mg and celecoxib 200 mg bid were associated with similar reductions in urinary excretion of PGI-M, whereas administration of naproxen 500 mg bid was associated with a significantly greater reduction in urinary excretion of PGI-M relative to the other treatments. These results imply that both COX-1 and COX-2 are important in the production of systemic PGI2.10,25,26 The clinical relevance of reductions in PGI-M in this and other studies is unclear. Although the kidney and the lung appear to be major sources of PGI-M, the relative contributions to the total amount excreted in urine from various tissue compartments remain an area of scientific investigation.27,28 Hence, this biomarker serves only as a measurement of total systemic PGI2 production.
Urinary TX-M is primarily derived from platelets. Similar to results from other trials,25,29 the lack of effect on urinary TX-M by etoricoxib 90 mg and celecoxib 200 mg bid relative to placebo or to the respective baseline values in this study suggests that thromboxane biosynthesis by platelets was not inhibited or stimulated. In contrast, as shown in a previous study,30 treatment with naproxen 500 mg bid significantly reduced TX-M excretion.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Because all NSAIDs have the potential to affect renal function to different extents, the present data further emphasize the importance of monitoring BP in all patients on chronic NSAID therapy.8
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was supported by Merck Research Laboratories. Jules I. Schwartz, Jutta Miller, David Hreniuk, Deborah A. Hilliard, Karen M. Snyder, Barry J. Gertz, and Keith M. Gottesdiener are employees of Merck Research Laboratories and own stock and/or hold stock options in the Company. Chau Thach, an employee of Merck Research Laboratories at the time of the conduct of the trial, is currently at Kos Pharmaceuticals. Kenneth M. Lasseter received grant support from Merck Research Laboratories for conduct of various phases of the study.
* On September 30, 2004, Merck & Co, Inc announced the voluntary worldwide withdrawal of rofecoxib from the market. 
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REFERENCES |
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