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Vol. 289, Issue 2, 735-741, May 1999
The EUPenn Group of Investigators at the Center for Experimental
Therapeutics,
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Conventional nonsteroidal anti-inflammatory drugs inhibit both
cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated
with nephrotoxicity. The present study was undertaken to assess the
renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older
adults (n = 36) were admitted to a clinical
research unit, placed on a fixed sodium intake, and randomized under
double-blind conditions to receive the specific Cox-2 inhibitor, MK-966
(50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor,
indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments
were well tolerated. Both active regimens were associated with a
transient but significant decline in urinary sodium excretion during
the first 72 h of treatment. Blood pressure and body weight did
not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the
prostacyclin metabolite 2,3-dinor-6-keto prostaglandin
F1
was decreased by both MK-966 and indomethacin and was
unchanged by placebo. Cox-2 may play a role in the systemic
biosynthesis of prostacyclin in healthy humans. Selective inhibition of
Cox-2 by MK-966 caused a clinically insignificant and transient
retention of sodium, but no depression of GFR. Inhibition of both Cox
isoforms by indomethacin caused transient sodium retention and a
decline in GFR. Our data suggest that acute sodium retention by
nonsteroidal anti-inflammatory drugs in healthy elderly subjects is
mediated by the inhibition of Cox-2, whereas depression of GFR is due
to inhibition of Cox-1.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
clinical benefits and adverse effects of aspirin and other nonsteroidal
anti-inflammatory drugs (NSAIDs) derive from inhibition of the enzyme
cyclooxygenase (Cox), the first step in the conversion of arachidonic
acid to prostaglandins (PGs), thromboxane (TX) A2, and prostacyclin
(PGI2). For many years, only a single form of Cox
was recognized. This isozyme, now referred to as Cox-1, is
constitutively expressed in platelets, the gastric mucosa, and most
tissues, where it is thought to exert "housekeeping" functions,
such as vascular homeostasis and gastric cytoprotection (Smith et al.,
1996
). The amino acid sequence of human Cox-2 is 60% homologous to
Cox-1. This isozyme is commonly termed "inducible," because it is
transiently expressed in response to inflammatory mediators, tumor
promoters, and growth factors (Hla and Neilson, 1992; Jones et al.,
1993; Smith et al., 1996). However, these definitions are likely to
oversimplify more complex regulatory mechanisms that govern expression
of the two isozymes. Thus, Cox-2 is present in the kidney and the brain
in the absence of inflammation (Harris et al., 1994; Guan et al., 1997;
Komhoff et al., 1997; Yang et al., 1997), whereas growth factor
induction and developmental regulation of the Cox-1
gene have been reported.
Conventional NSAIDs inhibit both Cox-1 and Cox-2 with limited
selectivity (Patrignani et al., 1994). It is generally assumed, albeit
with few supporting data, that their anti-inflammatory and analgesic
activity is mediated via Cox-2 inhibition (Zhang et al., 1997).
Inhibition of Cox-1, by contrast, is thought to be responsible for the
gastric toxicity and bleeding complications associated with NSAID
treatment. It is unclear whether NSAID-induced nephrotoxicity is
attributable to inhibition of Cox-1 or Cox-2. The intrarenal
distribution and regulation of Cox-2 by sodium intake strongly suggest
a role for this enzyme in renal physiology (Harris et al., 1994; Guan
et al., 1997; Komhoff et al., 1997; Yang et al., 1997) and emphasize
the need to clarify the renal effects of selective Cox-2 inhibitors
that are at an advanced stage of clinical development. Notably, one
such compound, flosulide, has been withdrawn from clinical development
because of a high incidence of peripheral edema (Emery, 1996). The
present study was undertaken to assess the renal effects of the
specific Cox-2 inhibitor, MK-966, during a 2-week administration to
elderly subjects. This is a target population for these drugs and one
that is the most susceptible to NSAID-induced nephrotoxicity. Sodium
excretion and other indices of renal function were assessed under
conditions of controlled sodium intake. We hypothesized that the effect
of MK-966 on urinary sodium excretion would be comparable to that of a
dual Cox-1/Cox-2 inhibitor, such as indomethacin.
Although we expected that selective inhibition of Cox-2 would fail to
reduce urinary 11-dehydro-TXB2 (TX-M) and serum
TXB2 indices of Cox-1-dependent thromboxane biosynthesis by
platelets, we also wished to address the hypothesis that prostacyclin
biosynthesis, as reflected by urinary excretion of 2,3-dinor-6-keto
PGF1 (PGI-M), its major metabolite in vivo
(FitzGerald et al., 1981; Brash et al., 1983), also would be unaffected
by inhibition of Cox-2.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Human Subjects. The study protocol was approved by the Institutional Review Board of the University of Pennsylvania, the Advisory Committee of the General Clinical Research Center at the Hospital of the University of Pennsylvania, and the Southern Institutional Review Board (Miami, FL). Thirty-six subjects were enrolled in the study. Stratification by gender and race (African Americans versus Caucasians/others) ensured a balance for these baseline characteristics. Subjects eligible for inclusion in the study were between 59 and 80 years of age. They were judged to be in good health for their age based on medical history, physical examination, and routine hematology and biochemistry. Subjects requiring pharmacologic treatment for hypertension or diabetes mellitus were excluded from participation in the study. Other exclusion criteria included serum creatinine > 2 mg/dl and creatinine clearance < 50 ml/min. All participants gave written informed consent, refrained from smoking, and did not consume any medications containing aspirin or other NSAIDs for at least 2 weeks before and during the trial.
All study subjects were confined to the General Clinical Research Center or the Clinical Pharmacology Associates Research Unit for a minimum of 17 days and adhered to a fixed 200-mEq sodium (~0.8 g/kg protein, 60-80 mEq potassium, ~350 mg of magnesium, 800 mg of calcium, isocaloric) diet, prepared by the metabolic kitchen. This was started at least 5 days before dosing and continued for the entire duration of the study. Only patients in sodium balance on the metabolic ward (based on weight within 1.0 kg for 2 consecutive days and 24-h urinary sodium between 180 and 220 mEq) were allowed to commence the study. Study discontinuation was required for all subjects whose serum creatinine, blood pressures, or body weight increased above prespecified safety values.Interventions.
Study subjects were randomized under
double-blind conditions to receive 50 mg of MK-966 every day (q.d.;
8:00 AM), 50 mg of indomethacin t.i.d. (8:00 AM, 3:00 PM, and 11:00
PM), or matching placebo for 2 weeks. The dosage of MK-966 was selected
on the basis of previous studies. A dose-ranging study in postsurgical dental pain showed that a single dose of 50 mg was the minimal dose
required to provide maximal analgesic efficacy (Ehrich et al., 1996a).
In addition, in a pilot study of the treatment of osteoarthritis of the
knee, 25 mg once daily for 6 weeks was indistinguishable from 125 mg
for all primary efficacy endpoints. Thus, the dose chosen for this
study is twice the maximum dose needed for chronic treatment of
osteoarthritis (Ehrich et al., 1997). The dose of indomethacin chosen
for the study is the standard dose used for chronic anti-inflammatory,
analgesic treatment.
Efficacy and Safety Assessments.
Twenty-four-hour urine
collections (8:00 AM to 8:00 AM) were performed daily for the
assessment of sodium and potassium excretion. Glomerular filtration
rate (GFR) was assessed by iohexol clearance on day 
1 and day 14. Creatinine clearance also was measured throughout the study. Urinary
excretion of N-acetyl-
-glucosaminidase (Boehringer Mannheim Biochemica, Indianapolis, IN), an index of renal proximal tubular dysfunction, was measured on day 2 and day 13. Blood pressure
(three measurements after 10-min supine rest) was measured every 4 h (from 8:00 AM to 8:00 PM). Body weight was measured daily (8:00 AM)
on a calibrated scale.
2, day 1, and day 13 for measurement of TX-M, an index of
Cox-1-dependent TX formation by platelets (FitzGerald et al., 1983;
Catella et al., 1986a; Catella and FitzGerald, 1987), 6 keto-PGF1, an index of the renal biosynthesis
of prostacyclin (Catella et al., 1986b), and PGI-M, an index of total
body biosynthesis of prostacyclin (FitzGerald et al., 1981, 1983; Brash
et al., 1983; Catella et al., 1986b). Urinary eicosanoids were measured by negative ion chemical ionization-gas chromatography/mass
spectrometry (NICI-GC/MS) using authentic deuterated standards (Lawson
et al., 1985, 1986; Catella et al., 1989; Catella and FitzGerald,
1990). In a subgroup of subjects, NICI-GC/MS also was applied to the measurement of serum TXB2, an index of the
capacity of the platelets to convert arachidonic acid through the Cox-1
pathway during whole-blood clotting (Patrono et al., 1980). Serum
TXB2 was measured at baseline and 4 h
postdosing on day 1. Deuterated Tx-M, 6 keto-PGF1, and TxB2 were
obtained from Cayman Chemical Co., Inc. (Ann Arbor, MI). Deuterated
PGI-M was obtained from Biomol Research Laboratories, Inc. (Plymouth
Meeting, PA).
Statistical Analysis. The primary hypothesis of the study was that MK-966 and indomethacin would produce similar levels of mean reduction in urinary sodium excretion from baseline during the first 72 h of treatment. This assertion was evaluated by an ANOVA appropriate for a three-factor experimental design with repeated measures over Time (Pre- versus Post-) and nonrepeated classifications of Treatment and Center. Model specification allowed for tests of significance of second-order interactions for Treatment × Center and Treatment × Time. Homogeneity of variance and normality assumptions were evaluated by the Shapiro-Wilk test and Levene's test, respectively. In addition to means and S.D. values for pre- and posttreatment time points, means of posttreatment measures adjusted for their corresponding values and associated S.E. values were tabulated for all variables except for serum TXB2 (no ANOVA was performed on this variable because of the small sample size).
A sample size of 12 subjects per treatment group was recruited for this study. We anticipated that if the mean reduction in urinary sodium excretion during the first 72 h for patients receiving 50 mg of MK-966 q.d. was equal to that for patients receiving 50 mg of indomethacin t.i.d., then this sample size would provide 80% probability that a 90% confidence interval for the difference would fall within the prespecified similarity limits of ±90 mEq.| |
Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Age, weight, systolic and diastolic blood pressure, and serum
creatinine and creatinine clearance of the three treatment groups at
baseline are reported in Table 1.
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All treatments were well tolerated. All subjects completed the study according to the protocol, with the exception of one patient in the indomethacin group, who was discontinued prematurely because of increasing anxiety. One subject on MK-966 had a mild increase of serum transaminases that resolved upon drug discontinuation.
Both active treatments (MK-966 and indomethacin) significantly reduced
net urinary sodium excretion during the first 72 h of treatment
compared with baseline (Fig. 1). MK-966
and indomethacin were not different (p = 0.35) with
respect to their effects on this parameter. In both groups, the
sodium-retaining effect was short-lived, largely disappearing by day 3 (Fig. 2), and the urinary sodium
excretion at day 7 was not different from baseline for all treatment
groups. However, in indomethacin-treated subjects, sodium excretion
declined again on day 14 (least-squares mean change from
baseline = 36.6 ± 13.4 mEq/24 h; p < .05). A trend toward delayed sodium retention also was present in the
placebo (least-squares mean change from baseline = 10 ± 12.9 mEq/24 h) and in the MK-966 group (least-squares mean change from
baseline = 8.1 ± 12.7 mEq/24 h). Also, the
between-treatment comparisons showed that the effect of indomethacin on
sodium excretion at day 14 was not different from placebo
(p = .169) or MK-966 (p = .134). The
change from baseline for the daily average urinary sodium excretion
during the 14 days of treatment was significantly greater with
indomethacin when compared with both MK-966 (p < .05)
and placebo (p < .005). The mean change over the 14 days of MK-966 treatment was not different from placebo.
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There were no significant changes in any treatment group in the daily average urinary excretion of potassium during the first week or during the entire 2-week treatment period. Urinary excretion of potassium on days 7 and 14 also was unchanged by the three treatments. The urinary potassium excretion during the first 72 h of treatment was not modified by placebo or indomethacin. However, a decrease (from 146.5 ± 23.6 mEq/72 h to 136.8 ± 21.6 mEq/72 h) was observed in the MK-966 group. Even though statistically significant by ANOVA (p < .05), this drop failed to reach significance by univariate analysis. Also, there was no difference between MK-966 and placebo (p = .246) or MK-966 and indomethacin (p = .152) in the between-treatment comparisons.
Body weight was not changed significantly by either of the active treatments or by placebo. At day 14, systolic blood pressure increased slightly from 129.4 ± 9.6 mm Hg to 135.0 ± 13.0 mm Hg in the MK-966 group, from 124.9 ± 12.9 mm Hg to 130.3 ± 11.9 mm Hg in the indomethacin group, and from 125.2 ± 11.2 mm Hg to 126.9 ± 16.4 mm Hg in the placebo group. None of these changes reached statistical significance in the within-treatment ANOVA or in the between-treatment comparisons. A similar trend toward a rise in diastolic blood pressure occurred at day 14. The least-squares mean change from baseline at day 14 was 1.7 ± 1.5, 2.6 ± 1.5, and 1.6 ± 1.6 mm Hg in the placebo, MK-966, and indomethacin groups, respectively. All changes failed to attain significance.
The GFR, as assessed by iohexol clearance, decreased after 2 weeks of
indomethacin, but was not changed significantly by MK-966 treatment or
placebo (Fig. 3). The effect of
indomethacin on iohexol clearance was significantly different from that
of placebo (p = .014) and MK-966 (p = .004). Creatinine clearance was also decreased after 2 weeks of
indomethacin (from 86.03 ± 21.01 ml/min to 75.52 ± 26.51 ml/min; p < .05), but was not affected significantly
by MK-966 treatment (from 90.90 ± 23.20 ml/min to 95.03 ± 21.48 ml/min; p is not significant) or placebo (from
98.13 ± 24.26 ml/min to 90.92 ± 31.82 ml/min; p
is not significant). The effect of indomethacin on creatinine clearance
was significantly different from that of MK-966 (p < .05) but was not different from placebo (p = 0.57).
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Renal tubular function was assessed by measurement of urinary
N-acetyl--glucosaminidase excretion. None of the
treatments significantly altered this parameter.
Urinary excretion of TX-M, an index of Cox-1-dependent thromboxane
biosynthesis by platelets, was decreased by 59.9 ± 16.6% (percentage of change least-squares mean ± S.E.M.) on
indomethacin, but was not changed significantly by MK-966 (+1.74 ± 15.2% change least-squares mean ± S.E.M.) or placebo
(+11.1 ± 13.8% change least-squares mean ± S.E.M.). The
decrease in TX-M excretion was statistically significant only in the
indomethacin group (p < .05) by ANOVA (Fig.
4). There were no differences between the effects of MK-966 and placebo treatments (p = .652),
whereas the effects of indomethacin on TX-M excretion were
significantly different both from placebo (p = .002)
and MK-966 (p = .017).
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Selectivity of MK-966 for the Cox-2 isozyme also was confirmed by
measurement of serum TXB2 in a subgroup of
subjects. Serum TXB2, an index of the capacity of
the platelets to synthesize TX via Cox-1, was not changed significantly
by MK-966 (+10.8 ± 21.3% change from baseline; n = 3) or placebo (42 ± 21.8% change from baseline;
n = 5), whereas it was nearly completely inhibited by
indomethacin (96.3 ± 1.4% change from baseline;
n = 5) 4 h after dosing on day 1.
Urinary 6 keto-PGF1 and PGI-M were inhibited
by indomethacin and MK-966, but were not affected significantly by
placebo (Figs. 5 and
6). The least-squares mean change from
baseline for urinary PGI-M was 64.8 ± 10.8 (p < .05), 73.6 ± 9.1 (p < .05), and 0.27 ± 9.1 pg/mg creatinine (p < .05) in the indomethacin, MK-966, and placebo groups, respectively. There were no differences between MK-966 and indomethacin with respect to their inhibitory effects on urinary PGI-M excretion (p = .55).
Similarly, the least-squares mean change from baseline for urinary
6-keto PGF1 was 25.3 ± 7.0 (p < .05), 27.1 ± 6.3 (p < .05), and 2.03 ± 6.4 pg/mg creatinine (p < .05)
in the indomethacin, MK-966, and placebo groups, respectively.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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It is unclear whether NSAID-induced renal toxicity is attributable
to inhibition of Cox-1 or Cox-2. Both Cox isoforms are constitutively
expressed in the kidney. However, Cox-1 mRNA is widely distributed,
whereas expression of Cox-2 in the rat renal cortex is localized to the
macula densa and surrounding cells of the cortical thick ascending
limbs (Harris et al., 1994; Guan et al., 1997; Komhoff et al., 1997;
Yang et al., 1997), which play a key role in the regulation of vascular
tone and renin release. In the rabbit kidney, Cox-2 mRNA expression is
present in the macula densa and in the interstitial cells of the outer
medulla (Guan et al., 1997). In these cells, which may play an
important role in regulating salt and water excretion, Cox-2 expression predominates over Cox-1 (Guan et al., 1997). In contrast to the rat and
rabbit, Cox-2 is not expressed in the macula densa in human kidney, but
is predominantly expressed intraglomerularly in podocytes (Komhoff et
al., 1997). Thus, Cox-2 in humans might regulate glomerular
hemodynamics by contracting the podocytes. Yang et al. (1997) have
reported that expression of Cox-2 is regulated in a cell-specific
fashion in response to altered sodium intake, whereas Cox-1 expression
is not influenced by dietary salt. Restriction of dietary sodium
increases Cox-2 in the rat renal cortex, particularly in the macula
densa, suggesting that this enzyme may play an important role in the
homeostatic regulation of renal perfusion and glomerular hemodynamics.
In contrast, a high-salt diet increases expression of Cox-2 in the
renal medulla, supporting a role for Cox-2 in the regulation of sodium
and water excretion (Yang et al., 1997).
Cox-2 also plays an important role in renal development in mice
(Dinchuk et al., 1995; Morham et al., 1995). Deletion of the Cox-2 gene in mice results in severe nephropathy (Dinchuk et
al., 1995; Morham et al., 1995). However, the renal localization and the temporal pattern of expression of the two Cox enzymes in human fetal kidney suggest that murine Cox-2 knockout data may not
be applicable to humans (Komhoff et al., 1997).
Little is known about the selective roles of the Cox isoforms in
humans. However, the studies in animals raise the possibility of
adverse renal effects of selective Cox-2 inhibition in humans. To
investigate this possibility we selected a dose of a Cox-2 inhibitor
that has been shown to be biochemically selective (Ehrich et al.,
1996b) and an effective analgesic in humans (Ehrich et al., 1996a). The
dose of MK-966 chosen for this study is twice the maximum dose needed
for chronic treatment of osteoarthritis (Ehrich et al., 1997).
Nephrotoxicity induced by conventional NSAIDs is most commonly
characterized by impaired GFR and/or an acute decrease in sodium excretion (Murray and Brater, 1993; Nies, 1998). The decline in sodium
excretion may result from reduced renal blood flow or from a direct
inhibition on sodium absorption independent of renal hemodynamics. This
study demonstrates that, in healthy elderly subjects, the decline in
GFR observed during short-term NSAID therapy appears attributable to
inhibition of Cox-1. In this population, an early, transient decline in
sodium excretion occurred without a change of GFR, suggesting that it
resulted from inhibition of Cox-2 in the renal tubules.
Sodium retention induced by MK-966 at a dose that was selective for inhibition of Cox-2 was short-lived and was not accompanied by a significant rise in blood pressure or body weight. The effects of selective Cox-2 inhibition in subjects with hypertension and/or impaired renal function remain to be established. Therefore, although the results of the present study indicate that short-term administration of MK-966 is not associated with impaired GFR or renal toxicity, they pertain only to healthy, elderly patients on a fixed intake of sodium.
The study population followed a constant 200-mEq sodium diet. This daily sodium intake is estimated to represent the typical American diet, even though it greatly exceeds the recommended minimum requirement of 20 mEq daily. The effects of Cox-2 inhibition under renoprival conditions that would activate the renin-angiotensin system are unknown and merit further investigation.
The effects on urinary excretion of TX-M and serum
TXB2 demonstrate that the dose of MK-966 that we
studied (50 mg q.d.) has no effect on Cox-1-dependent thromboxane
biosynthesis by platelets. By contrast, specific Cox-2 inhibition
resulted in partial suppression of both renal and extrarenal
biosynthesis of prostacyclin. Urinary excretion of 6 keto-PGF1, an index of renal biosynthesis of
prostacyclin (Catella et al., 1986b), and PGI-M, an index of total body
biosynthesis of prostacyclin (FitzGerald et al., 1981, 1983; Brash et
al., 1983; Catella et al., 1986b), both were inhibited similarly by
MK-966 and indomethacin. Cox-2 is constitutively expressed in the rat,
rabbit, and human kidney (Harris et al., 1994; Guan et al., 1997;
Komhoff et al., 1997; Yang et al., 1997), and it is conceivable that it
contributes to prostacyclin synthesis by the kidney under physiological
conditions. However, systemic infusion of prostacyclin increases
urinary 6 keto-PGF1 as well as urinary PGI-M
(Brash et al., 1983). Therefore, the suppressive effects of both
indomethacin and MK-966 on 6 keto-PGF1 may merely reflect inhibition of the extrarenal contribution to excretion of the hydrolysis product in urine.
An additional finding of this study was the suggestion that extrarenal
biosynthesis of prostacyclin also was mediated by Cox-2. This was
unexpected because Cox-1, but not Cox-2, is expressed constitutively by
endothelial and vascular smooth muscle cells in vitro (Smith et al.,
1996). One possible explanation may be related to the finding that
laminar shear stress up-regulates Cox-2 in vascular endothelium in
vitro (Topper et al., 1996). A further contribution from Cox-2 might be
expected in advancing age and in syndromes of platelet activation and
inflammation, where prostacyclin biosynthesis, as reflected by
excretion of urinary PGI-M, is augmented (FitzGerald et al., 1984;
Reilly and FitzGerald, 1986; Bernard et al., 1991). Thus, prothrombotic
and inflammatory stimuli induce Cox-2 expression and prostacyclin generation by vascular tissues in vitro (Hla and Neilson, 1992; Jones
et al., 1993). Furthermore, the arachidonic acid in microparticles shed
from activated platelets can up-regulate Cox-2 expression in
endothelial cells and be used as a substrate for increased prostacyclin
biosynthesis (Barry et al., 1997). It is also formally possible that
the inhibition of urinary PGI-M by MK-966 reflects a property of MK-966
in addition to, but distinct from, its capacity to inhibit Cox-2.
MK-966 might inhibit -oxidation of prostanoids, therefore shifting
the metabolism of prostacyclin toward other products. The possibility
that MK-966 might directly reduce the renal clearance of PGI-M also has
not been excluded.
Prostacyclin is the major Cox product of macrovascular endothelium in
vitro. Although it is a potent modulator of platelet function and
vascular tone in vitro, its importance in vivo has been speculative.
Thus, although the effects of prostacyclin appear to be mediated by a
single-membrane G protein-coupled receptor, the absence of receptor
antagonists have made it difficult to assess the role of this
eicosanoid in integrated systems. However, Narumiya and coworkers
(Murata et al., 1997) have reported that inactivation of the
prostacyclin receptor gene results in an increased susceptibility to
thrombosis in vivo. Although these results provide the first evidence
for the homeostatic antithrombotic effect of endogenous prostacyclin in
vivo, infusion of exogenous prostacyclin is an effective platelet
inhibitor in vivo, albeit limited by gastrointestinal and vasoactive
side effects (FitzGerald et al., 1979; Belch et al., 1995).
Pharmacological enhancement of endogenous prostacyclin is also an
effective antithrombotic strategy in vivo. Thus, adenoviral delivery of
Cox-1 to canine coronary vasculature prevents platelet activation in
vivo (Wu, 1997). Similarly, these results are consistent with
experimental data that demonstrate that the antithrombotic effect of
combining thromboxane synthase inhibitors with thromboxane receptor
antagonists is largely attributable to augmented prostacyclin formation
(Fitzgerald et al., 1988).
Presently, the implications of prostacyclin suppression in vivo are
unclear. Results from prostacyclin receptor knockout mice would suggest
that prevention of prostacyclin formation might be expected to
contribute to, if not explain, the anti-inflammatory and analgesic
effects of such compounds (Murata et al., 1997). Prostacyclin formation
by the vasculature is of functional importance in limiting the response
to a thrombotic insult in mice, and we have shown previously that
urinary excretion of PGI-M is increased in syndromes of platelet
activation (Fitzgerald et al., 1986). It remains to be established
whether treatment with specific Cox-2 inhibitors will suppress this response.
In conclusion, our results suggest that Cox-2 plays a role in the biosynthesis of prostacyclin under physiological conditions in humans, at least in healthy, elderly subjects on a controlled intake of sodium. In these subjects, MK-966 inhibited Cox-2 selectively, and this resulted in a clinically insignificant and transient retention of sodium, but no depression of GFR. Given the known renal effects of NSAIDs, it seems likely that Cox-2 inhibition causes acute sodium retention, whereas the decline in GFR is attributable to the blockade of Cox-1.
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Acknowledgments |
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We recognize and thank Mrs. Barbara Tournier, R.N., M.S.N., and Stephanie Green, R.D., for their expertise, efforts, and contribution.
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Footnotes |
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Accepted for publication December 22, 1998.
Received for publication October 19, 1998.
1 This work was supported in part by Grants HL 57847 and M01RR00040 from the National Institutes of Health and by funds from Merck & Co. G.A.F. is the Robinette Foundation Professor of Cardiovascular Medicine. Abstracts have been presented at the Vascular Biology Meeting (American Heart Association) in San Francisco in April and at the Second International Workshop on Cox-2 in Maui in July of this year.
2 F.C-L. and B.M. have contributed equally to the design and execution of the study.
3 Present address: Vanderbilt University, Nashville, TN 37232.
Send reprint requests to: Francesca Catella-Lawson, M.D., University of Pennsylvania, GCRC, 160 Dulles Building, 3400 Spruce St., Philadelphia, PA 19104. E-mail: francesca{at}spirit.GCRC.upenn.edu
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Abbreviations |
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Cox, cyclooxygenase;
GFR, glomerular filtration
rate;
NSAID, nonsteroidal inflammatory drug;
NICI-GC/MS, negative ion
chemical ionization-gas chromatography/mass spectrometry;
PG, prostaglandin;
PGI2, prostacyclin;
PGI-M, 2,3-dinor-6-keto
PGF1;
TX, thromboxane;
TX-M, 11-dehydrothromboxane
2;
TXB2, thromboxane 2;
q.d., every
day.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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A. Aneja and M. E. Farkouh Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema? Therapeutic Advances in Cardiovascular Disease, February 1, 2008; 2(1): 53 - 66. [Abstract] [PDF]
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D. Sankaran, N. Bankovic-Calic, M. R. Ogborn, G. Crow, and H. M. Aukema Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease Am J Physiol Renal Physiol, September 1, 2007; 293(3): F821 - F830. [Abstract] [Full Text] [PDF]
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M. L. Capone, S. Tacconelli, M. G. Sciulli, P. Anzellotti, L. Di Francesco, G. Merciaro, P. Di Gregorio, and P. Patrignani Human Pharmacology of Naproxen Sodium J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 453 - 460. [Abstract] [Full Text] [PDF]
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 T. Klein, M. Eltze, T. Grebe, A. Hatzelmann, and M. Komhoff Celecoxib dilates guinea-pig coronaries and rat aortic rings and amplifies NO/cGMP signaling by PDE5 inhibition Cardiovasc Res, July 15, 2007; 75(2): 390 - 397. [Abstract] [Full Text] [PDF]
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G. Salinas, U. C. Rangasetty, B. F. Uretsky, and Y. Birnbaum The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 98 - 111. [Abstract] [PDF]
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S. J. Hewett, J. M. Silakova, and J. A. Hewett Oral Treatment with Rofecoxib Reduces Hippocampal Excitotoxic Neurodegeneration J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1219 - 1224. [Abstract] [Full Text] [PDF]
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J. Zhang, E. L. Ding, and Y. Song Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia Events: Meta-analysis of Randomized Trials JAMA, October 4, 2006; 296(13): 1619 - 1632. [Abstract] [Full Text] [PDF]
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H. I. Abdullah, P. L. Pedraza, S. Hao, K. D. Rodland, J. C. McGiff, and N. R. Ferreri NFAT regulates calcium-sensing receptor-mediated TNF production Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1110 - F1117. [Abstract] [Full Text] [PDF]
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M. Hermann and F. Ruschitzka Novel anti-inflammatory drugs in hypertension Nephrol. Dial. Transplant., April 1, 2006; 21(4): 859 - 864. [Full Text] [PDF]
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J. Jermany, J. Branson, R. Schmouder, M. Guillaume, and C. Rordorf Lumiracoxib Does Not Affect the Ex Vivo Antiplatelet Aggregation Activity of Low-Dose Aspirin in Healthy Subjects J. Clin. Pharmacol., October 1, 2005; 45(10): 1172 - 1178. [Abstract] [Full Text] [PDF]
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T. Kurth, C. H. Hennekens, T. Sturmer, H. D. Sesso, R. J. Glynn, J. E. Buring, and J. M. Gaziano Analgesic Use and Risk of Subsequent Hypertension in Apparently Healthy Men Arch Intern Med, September 12, 2005; 165(16): 1903 - 1909. [Abstract] [Full Text] [PDF]
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B. F. McAdam, D. Byrne, J. D. Morrow, and J. A. Oates Contribution of Cyclooxygenase-2 to Elevated Biosynthesis of Thromboxane A2 and Prostacyclin in Cigarette Smokers Circulation, August 16, 2005; 112(7): 1024 - 1029. [Abstract] [Full Text] [PDF]
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P. A. Konstantinopoulos and D. F. Lehmann The Cardiovascular Toxicity of Selective and Nonselective Cyclooxygenase Inhibitors: Comparisons, Contrasts, and Aspirin Confounding J. Clin. Pharmacol., July 1, 2005; 45(7): 742 - 750. [Abstract] [Full Text] [PDF]
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 R. D. Rudic, D. Brinster, Y. Cheng, S. Fries, W.-L. Song, S. Austin, T. M. Coffman, and G. A. FitzGerald COX-2-Derived Prostacyclin Modulates Vascular Remodeling Circ. Res., June 24, 2005; 96(12): 1240 - 1247. [Abstract] [Full Text] [PDF]
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K. K. Wu, J.-Y. Liou, and K. Cieslik Transcriptional Control of COX-2 via C/EBP{beta} Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 679 - 685. [Abstract] [Full Text] [PDF]
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F. T. Shaya, S. W. Blume, C. M. Blanchette, M. R. Weir, and C. D. Mullins Selective Cyclooxygenase-2 Inhibition and Cardiovascular Effects: An Observational Study of a Medicaid Population Arch Intern Med, January 24, 2005; 165(2): 181 - 186. [Abstract] [Full Text] [PDF]
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K. Rabausch, E. Bretschneider, M. Sarbia, J. Meyer-Kirchrath, P. Censarek, R. Pape, J. W. Fischer, K. Schror, and A.-A. Weber Regulation of Thrombomodulin Expression in Human Vascular Smooth Muscle Cells by COX-2-Derived Prostaglandins Circ. Res., January 7, 2005; 96(1): e1 - e6. [Abstract] [Full Text] [PDF]
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M. A. Buerkle, S. Lehrer, H.-Y. Sohn, P. Conzen, U. Pohl, and F. Krotz Selective Inhibition of Cyclooxygenase-2 Enhances Platelet Adhesion in Hamster Arterioles In Vivo Circulation, October 5, 2004; 110(14): 2053 - 2059. [Abstract] [Full Text] [PDF]
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T. Zewde and D. L. Mattson Inhibition of Cyclooxygenase-2 in the Rat Renal Medulla Leads to Sodium-Sensitive Hypertension Hypertension, October 1, 2004; 44(4): 424 - 428. [Abstract] [Full Text] [PDF]
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C.-M. Hao and M. D. Breyer Hypertension and Cyclooxygenase-2 Inhibitors: Target: The Renal Medulla Hypertension, October 1, 2004; 44(4): 396 - 397. [Full Text] [PDF]
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G. L. Braden, M. H. O'shea, J. G. Mulhern, and M. J. Germain Acute renal failure and hyperkalaemia associated with cyclooxygenase-2 inhibitors Nephrol. Dial. Transplant., May 1, 2004; 19(5): 1149 - 1153. [Abstract] [Full Text] [PDF]
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K. L. Therland, J. Stubbe, H. C. Thiesson, P. D. Ottosen, S. Walter, G. L. Sorensen, O. Skott, and B. L. Jensen Cycloxygenase-2 Is Expressed in Vasculature of Normal and Ischemic Adult Human Kidney and Is Colocalized with Vascular Prostaglandin E2 EP4 Receptors J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1189 - 1198. [Abstract] [Full Text] [PDF]
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 M J James and L G Cleland Applying a research ethics committee approach to a medical practice controversy: the case of the selective COX-2 inhibitor rofecoxib J. Med. Ethics, April 1, 2004; 30(2): 182 - 184. [Abstract] [Full Text]
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 T. R. Hegi, T. Bombeli, B. Seifert, P. C. Baumann, U. Haller, M. P. Zalunardo, T. Pasch, and D. R. Spahn Effect of rofecoxib on platelet aggregation and blood loss in gynaecological and breast surgery compared with diclofenac Br. J. Anaesth., April 1, 2004; 92(4): 523 - 531. [Abstract] [Full Text] [PDF]
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M. L. Capone, S. Tacconelli, M. G. Sciulli, M. Grana, E. Ricciotti, P. Minuz, P. Di Gregorio, G. Merciaro, C. Patrono, and P. Patrignani Clinical Pharmacology of Platelet, Monocyte, and Vascular Cyclooxygenase Inhibition by Naproxen and Low-Dose Aspirin in Healthy Subjects Circulation, March 30, 2004; 109(12): 1468 - 1471. [Abstract] [Full Text] [PDF]
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H.-F. Cheng and R. C. Harris Cyclooxygenases, the Kidney, and Hypertension Hypertension, March 1, 2004; 43(3): 525 - 530. [Abstract] [Full Text] [PDF]
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M. Izhar, T. Alausa, A. Folker, E. Hung, and G. L. Bakris Effects of COX Inhibition on Blood Pressure and Kidney Function in ACE Inhibitor-Treated Blacks and Hispanics Hypertension, March 1, 2004; 43(3): 573 - 577. [Abstract] [Full Text] [PDF]
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O. A. Belton, A. Duffy, S. Toomey, and D. J. Fitzgerald Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis Circulation, December 16, 2003; 108(24): 3017 - 3023. [Abstract] [Full Text] [PDF]
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A. Haider, I. Lee, J. Grabarek, Z. Darzynkiewicz, and N. R. Ferreri Dual Functionality of Cyclooxygenase-2 as a Regulator of Tumor Necrosis Factor-Mediated G1 Shortening and Nitric Oxide-Mediated Inhibition of Vascular Smooth Muscle Cell Proliferation Circulation, August 26, 2003; 108(8): 1015 - 1021. [Abstract] [Full Text] [PDF]
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S. R. Baber, H. C. Champion, T. J. Bivalacqua, A. L. Hyman, and P. J. Kadowitz Role of Cyclooxygenase-2 in the Generation of Vasoactive Prostanoids in the Rat Pulmonary and Systemic Vascular Beds Circulation, August 19, 2003; 108(7): 896 - 901. [Abstract] [Full Text] [PDF]
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V. L. Ghafoor Management of Painful Conditions in the Elderly Journal of Pharmacy Practice, August 1, 2003; 16(4): 276 - 283. [Abstract] [PDF]
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C J Hawkey and M J S Langman Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors Gut, April 1, 2003; 52(4): 600 - 608. [Abstract] [Full Text] [PDF]
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D. L Johnson, T. M Hisel, and B. B. Phillips Effect of Cyclooxygenase-2 Inhibitors on Blood Pressure Ann. Pharmacother., March 1, 2003; 37(3): 442 - 446. [Abstract] [Full Text] [PDF]
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K. R. Kozak, B. C. Crews, J. D. Morrow, L.-H. Wang, Y. H. Ma, R. Weinander, P.-J. Jakobsson, and L. J. Marnett Metabolism of the Endocannabinoids, 2-Arachidonylglycerol and Anandamide, into Prostaglandin, Thromboxane, and Prostacyclin Glycerol Esters and Ethanolamides J. Biol. Chem., November 15, 2002; 277(47): 44877 - 44885. [Abstract] [Full Text] [PDF]
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F. Roig, M. T. Llinas, R. Lopez, and F. J. Salazar Role of Cyclooxygenase-2 in the Prolonged Regulation of Renal Function Hypertension, November 1, 2002; 40(5): 721 - 728. [Abstract] [Full Text] [PDF]
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M. S. Joy The Renal Effects of Traditional Nonsteroidal Anti-Inflammatory Agents Versus Cyclooxygenase-2 Inhibitors Journal of Pharmacy Practice, October 1, 2002; 15(5): 383 - 391. [Abstract] [PDF]
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T. Yang, S. J. Forrest, N. Stine, Y. Endo, A. Pasumarthy, H. Castrop, S. Aller, J. N. Forrest Jr., J. Schnermann, and J. Briggs Cyclooxygenase cloning in dogfish shark, Squalus acanthias, and its role in rectal gland Cl secretion Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R631 - R637. [Abstract] [Full Text] [PDF]
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C. R. McCrory and S. G. E. Lindahl Cyclooxygenase Inhibition for Postoperative Analgesia Anesth. Analg., July 1, 2002; 95(1): 169 - 176. [Full Text] [PDF]
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B. Hinz and K. Brune Cyclooxygenase-2---10 Years Later J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 367 - 375. [Abstract] [Full Text] [PDF]
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E. Connolly, D. J. Bouchier-Hayes, E. Kaye, A. Leahy, D. Fitzgerald, and O. Belton Cyclooxygenase Isozyme Expression and Intimal Hyperplasia in a Rat Model of Balloon Angioplasty J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 393 - 398. [Abstract] [Full Text] [PDF]
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F. Catella-Lawson, M. P. Reilly, S. C. Kapoor, A. J. Cucchiara, S. DeMarco, B. Tournier, S. N. Vyas, and G. A. FitzGerald Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin N. Engl. J. Med., December 20, 2001; 345(25): 1809 - 1817. [Abstract] [Full Text] [PDF]
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S. Verma, S. R. Raj, L. Shewchuk, K. J. Mather, and T. J. Anderson Cyclooxygenase-2 Blockade Does Not Impair Endothelial Vasodilator Function in Healthy Volunteers: Randomized Evaluation of Rofecoxib Versus Naproxen on Endothelium-Dependent Vasodilatation Circulation, December 11, 2001; 104(24): 2879 - 2882. [Abstract] [Full Text] [PDF]
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J. P. Killen, C. M. Nzerue, S. A. Rich, G. A. FitzGerald, and C. Patrono The Coxibs, Selective Inhibitors of Cyclooxygenase-2 N. Engl. J. Med., December 6, 2001; 345(23): 1708 - 1709. [Full Text] [PDF]
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D. Mukherjee, S. E. Nissen, and E. J. Topol Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors JAMA, August 22, 2001; 286(8): 954 - 959. [Abstract] [Full Text] [PDF]
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G. A. FitzGerald and C. Patrono The Coxibs, Selective Inhibitors of Cyclooxygenase-2 N. Engl. J. Med., August 9, 2001; 345(6): 433 - 442. [Full Text] [PDF]
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M. D. Fernandez, J. L. Z. Garcia, F. D. Garcia, S. Gupta, C. Bombardier, L. Laine, and A. Reicin Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen N. Engl. J. Med., May 3, 2001; 344(18): 1398 - 1399. [Full Text] [PDF]
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I. A. Mardini and G. A. FitzGerald Selective Inhibitors of Cyclooxygenase-2: A Growing Class of Anti-Inflammatory Drugs Mol. Interv., April 1, 2001; 1(1): 30 - 38. [Abstract] [Full Text]
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J. D. Imig Eicosanoid regulation of the renal vasculature Am J Physiol Renal Physiol, December 1, 2000; 279(6): F965 - F981. [Abstract] [Full Text] [PDF]
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M ostensen and P M Villiger Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus Lupus, October 1, 2000; 9(8): 566 - 572. [Abstract] [PDF]
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 S. J. Vane Aspirin and other anti-inflammatory drugs Thorax, October 1, 2000; 55(90002): 3S - 9. [Full Text]
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 F. A. Wollheim Selective Cox-2 inhibition in man--therapeutic breakthrough or cosmetic advance? Rheumatology, September 1, 2000; 39(9): 935 - 938. [Full Text] [PDF]
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O. Belton, D. Byrne, D. Kearney, A. Leahy, and D. J. Fitzgerald Cyclooxygenase-1 and -2-Dependent Prostacyclin Formation in Patients With Atherosclerosis Circulation, August 22, 2000; 102(8): 840 - 845. [Abstract] [Full Text] [PDF]
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 S. K. Swan, D. W. Rudy, K. C. Lasseter, C. F. Ryan, K. L. Buechel, L. J. Lambrecht, M. B. Pinto, S. C. Dilzer, O. Obrda, K. J. Sundblad, et al. Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet: A Randomized, Controlled Trial Ann Intern Med, July 4, 2000; 133(1): 1 - 9. [Abstract] [Full Text] [PDF]
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L. P. Audoly, B. Rocca, J.-E. Fabre, B. H. Koller, D. Thomas, A. L. Loeb, T. M. Coffman, and G. A. FitzGerald Cardiovascular Responses to the Isoprostanes iPF2{alpha}-III and iPE2-III Are Mediated via the Thromboxane A2 Receptor In Vivo Circulation, June 20, 2000; 101(24): 2833 - 2840. [Abstract] [Full Text] [PDF]
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A. Whelton, G. Schulman, C. Wallemark, E. J. Drower, P. C. Isakson, K. M. Verburg, and G. S. Geis Effects of Celecoxib and Naproxen on Renal Function in the Elderly Arch Intern Med, May 22, 2000; 160(10): 1465 - 1470. [Abstract] [Full Text] [PDF]
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W. Young, K. Mahboubi, A. Haider, I. Li, and N. R. Ferreri Cyclooxygenase-2 Is Required for Tumor Necrosis Factor-{alpha}- and Angiotensin II-Mediated Proliferation of Vascular Smooth Muscle Cells Circ. Res., April 28, 2000; 86(8): 906 - 914. [Abstract] [Full Text] [PDF]
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P. E. Lipsky, P. Brooks, L. J. Crofford, R. DuBois, D. Graham, L. S. Simon, L. B. A. van de Putte, and S. B. Abramson Unresolved Issues in the Role of Cyclooxygenase-2 in Normal Physiologic Processes and Disease Arch Intern Med, April 10, 2000; 160(7): 913 - 920. [Abstract] [Full Text] [PDF]
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E. M. Smyth, S. C. Austin, M. P. Reilly, and G. A. FitzGerald Internalization and Sequestration of the Human Prostacyclin Receptor J. Biol. Chem., October 6, 2000; 275(41): 32037 - 32045. [Abstract] [Full Text] [PDF]
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G. E. Caughey, L. G. Cleland, J. R. Gamble, and M. J. James Up-regulation of Endothelial Cyclooxygenase-2 and Prostanoid Synthesis by Platelets. ROLE OF THROMBOXANE A2 J. Biol. Chem., October 5, 2001; 276(41): 37839 - 37845. [Abstract] [Full Text] [PDF]
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D. Pratico, C. Tillmann, Z.-B. Zhang, H. Li, and G. A. FitzGerald Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice PNAS, March 13, 2001; 98(6): 3358 - 3363. [Abstract] [Full Text] [PDF]
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, placebo; 
, MK-966; 
,
indomethacin).
