J Gen Intern Med. 2005
Jan;20(1):62-7.
Valdecoxib for treatment of primary dysmenorrhea. A randomized,
double-blind comparison with placebo and naproxen.
Daniels SE, Torri S, Desjardins PJ.
Scirex Corporation, 3200 Red River, Suite 300, Austin, TX 78705,
USA.
OBJECTIVE: To compare the analgesic efficacy of valdecoxib with
placebo and naproxen sodium for relieving menstrual cramping and
pain due to primary dysmenorrhea. DESIGN: Single-center, double-blind
study with a 4-period, 4-sequence crossover design. Patients assessed
pain intensity and pain relief at regular intervals up to 12 hours
following the initial dose. SETTING: Privately owned outpatient
clinic. PATIENTS/PARTICIPANTS: One hundred twenty patients with
moderate to severe menstrual cramping were randomized. Eighty-seven
patients completed all treatment cycles. INTERVENTIONS: Valdecoxib
20 mg or 40 mg, naproxen sodium 550 mg, or placebo twice a day as
required for < or =3 days in a single menstrual cycle. MEASUREMENTS
AND MAIN RESULTs: Both doses of valdecoxib (20 and 40 mg) were comparable
to naproxen sodium and superior to placebo at all time points assessed
for each of the primary end points. Valdecoxib and naproxen sodium
had comparable onset and duration of action. Although the study
design allowed patients 2 doses per day, only 15% and 20% of patients
in the valdecoxib 20 mg and valdecoxib 40 mg groups, respectively,
required remedication within the first 12 hours. The incidence of
adverse events was similar between active and placebo groups. CONCLUSION:
Valdecoxib provided a fast onset of analgesic action, a level of
efficacy similar to naproxen sodium, and a high level of patient
satisfaction in the relief of menstrual pain due to primary dysmenorrhea.
Valdecoxib was effective and well tolerated and thus appears to
be a viable treatment for menstrual pain due to primary dysmenorrhea.
Drug Dev Ind Pharm. 2005 Jan;31(1):1-10.
Enhancement of dissolution rate of valdecoxib using solid dispersions
with polyethylene glycol 4000.
Liu C, Liu C, Desai KG.
Life Science College, Ocean University of China, Qingdao, China.
The aim of the present study was to enhance the dissolution rate
of valdecoxib using its solid dispersions (SDs) with polyethylene
glycol (PEG) 4000. The phase solubility behavior of valdecoxib
in the presence of various concentrations of PEG 4000 in water
was obtained at 37 degrees C. The solubility of valdecoxib increased
with increasing amount of PEG 4000 in water. Gibbs free energy
(deltaG(zero)tr) values were all negative, indicating the spontaneous
nature of valdecoxib solubilization, and they decreased with increase
in the PEG 4000 concentration, demonstrating that the reaction
conditions became more favorable as the concentration of PEG 4000
increased. The SDs of valdecoxib with PEG 4000 were prepared at
1:1, 1:2, 1:5, and 1:10 (valdecoxib: PEG 4000) ratio by melting
method. Evaluation of the properties of the SDs was performed
by using dissolution, Fourier-transform infrared (FTIR) spectroscopy,
differential scanning calorimetry (DSC), X-ray diffraction (XRD),
and scanning electron microscopy (SEM) studies. The SDs of valdecoxib
with PEG 4000 exhibited enhanced dissolution rate of valdecoxib,
and the rate increased with increasing concentration of PEG 4000
in SDs. Mean dissolution time (MDT) of valdecoxib decreased significantly
after preparation of SDs and physical mixture with PEG 4000. The
FTIR spectroscopic studies showed the stability of valdecoxib
and absence of well-defined valdecoxib-PEG 4000 interaction. The
DSC and XRD studies indicated the amorphous state of valdecoxib
in SDs of valdecoxib with PEG 4000. The SEM pictures showed the
formation of effective SDs of valdecoxib with PEG 4000, since
well-defined changes in the surface nature of valdecoxib, SDs,
and physical mixture were observed.
Bioorg Med Chem Lett. 2004 Dec 20;14(24):6001-6.
Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta
and gamma-class enzymes from Archaea with sulfonamides.
Zimmerman S, Innocenti A, Casini A, Ferry JG, Scozzafava A, Supuran
CT.
Department of Biochemistry and Molecular Biology, Eberly College
of Science, Pennsylvania State University, University Park, PA
16802-4500, USA.
A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1)
belonging to the beta- and gamma-families from Archaea with sulfonamides
has been performed. Compounds included in this study were the
clinically used sulfonamide CA inhibitors, such as acetazolamide,
methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib,
dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide
analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide
derivatives. The two gamma-CAs from Methanosarcina thermophila
(Zn-Cam and Co-Cam) showed very different inhibitory properties
with these compounds, as compared to the alpha-CA isozymes hCA
I, II, and IX, and the beta-CA from Methanobacterium thermoautotrophicum
(Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide,
with inhibition constants in the range of 63-96nM, whereas other
investigated aromatic/heterocylic sulfonamides showed a rather
levelled behavior, with K(I)s in the range of 0.12-1.70muM. The
best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide,
with K(I)s in the range of 0.12-0.13muM, whereas the worst one
was homosulfanilamide (K(I) of 8.50muM). In the case of Cab, the
inhibitory power of these compounds varied to a much larger extent,
with sulfamic acid and sulfamide showing millimolar affinities
(K(I)s in the range of 44-103mM), whereas the best inhibitor was
ethoxzolamide, with a K(I) of 5.35muM. Most of these sulfonamides
showed inhibition constants in the range of 12-100muM against
Cab. Thus, the three CA families investigated up to now possess
a very diverse affinity for sulfonamides, the inhibitors with
important medicinal, and environmental applications.
J Pharmacol Exp Ther. 2004 Oct 19.
Valdecoxib: Assessment of COX-2 potency and selectivity.
Gierse JK, Zhang Y, Hood WF, Walker MC, Trigg JS, Maziasz TJ,
Koboldt CM, Muhammad JL, Zweifel BS, Masferrer JL, Isakson PC,
Seibert K.
Pfizer.
The discovery of a second isoform of cyclooxygenase (COX) led
to the search for compounds that could selectively inhibit COX-2
in humans, while sparing prostaglandin formation from COX-1. Celecoxib
and rofecoxib were among the molecules developed from these efforts.
We report here the pharmacological properties of a third selective
COX-2 inhibitor, valdecoxib, which is the most potent and in vitro
selective of the marketed COX-2 inhibitors that we have studied.
Recombinant human COX-1 and COX-2 were used to screen for new
highly potent and in vitro selective COX-2 inhibitors and compare
kinetic mechanisms of binding and enzyme inhibition with other
COX inhibitors. Valdecoxib potently inhibits recombinant COX-2,
with an IC50 of 0.005 microM; this compares with IC50 values of
0.05 microM for celecoxib, 0.5 microM for rofecoxib and 2.1 microM
for etoricoxib. Unique binding interactions of valdecoxib with
COX-2 translate into a fast rate of inactivation of COX-2 110,000
M-1 sec-1 (compared to 7,000 M-1 sec-1 for rofecoxib and 80 M-1
sec-1 for etoricoxib). The overall saturation binding affinity
for COX-2 of valdecoxib is 2.6 nM (compared to 1.6 nM for celecoxib,
51 nM for rofecoxib and 260 nM for etoricoxib), with a slow off
rate (t1/2 ~ 98 min). Valdecoxib inhibits COX-1 in a competitive
fashion only at very high concentrations (IC50 = 150 uM). Collectively,
these data provide a mechanistic basis for the potency and in
vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar
activity in the human whole blood COX assay (COX-2 IC50 = 0.24
uM; COX-1 IC50 = 21.9 uM). We also determined whether this in
vitro potency and selectivity translated to significant potency
in vivo. In rats valdecoxib demonstrated marked potency in acute
and chronic models of inflammation (air pouch ED50 = 0.06 mg/kg;
paw edema ED50 = 5.9 mg/kg; adjuvant arthritis ED50 = 0.03 mg/kg).
In these same animals, COX-1 was spared at doses greater than
200 mg/kg. These data provide a basis for the observed potent
anti-inflammatory activity of valdecoxib in humans.
Clin Ther. 2004 Aug;26(8):1249-60.
Effects of valdecoxib in the treatment of chronic low back pain:
results of a randomized, placebo-controlled trial.
Coats TL, Borenstein DG, Nangia NK, Brown MT.
Benchmark Research, Austin, Texas 78705, USA.
BACKGROUND: Valdecoxib, a cyclooxygenase (COX)-2 specific inhibitor,
is indicated for relief of the signs and symptoms of rheumatoid
arthritis, osteoarthritis, and primary dysmenorrhea. Therapeutic
doses of COX-2 specific inhibitors are as effective as nonspecific
nonsteroidal anti-inflammatory drugs in reducing inflammatory
pain while sparing the gastrointestinal and platelet toxicity
associated with nonspecific COX-1 inhibition. OBJECTIVE: The aim
of this study was to assess the analgesic efficacy and tolerability
of valdecoxib 40 mg/d compared with placebo in the treatment of
chronic low back pain. METHODS: This 4-week, prospective, randomized,
double-blind placebo-controlled, parallel-group study was conducted
at 37 centers across the United States and 5 centers in Canada.
Patients aged > or =18 years with chronic low back pain in
flare were enrolled. Patients were randomized to receive valdecoxib
40-mg/d or placebo tablets, once daily for 4 weeks. Patients rated
low back pain intensity on a visual analog scale and completed
the Roland-Morris Disability Questionnaire and the modified Brief
Pain Inventory-Short Form (mBPI-SF) at each visit. RESULTS: Two
hundred ninety-three patients were enrolled. The valdecoxib group
comprised 148 patients (81 women, 67 men; mean [SD] age, 48.6
[13.3] years; mean [SD] body weight, 86.6 [20.9] kg), and the
placebo group included 145 patients (85 women, 60 men; mean [SD]
age, 48.7 [12.6] years; mean [SD] body weight, 85.6 [19.9] kg).
Of the enrolled patients, 249 completed the study: 134 patients
(91%) who received valdecoxib and 115 patients (79%) who received
placebo. No statistically significant differences in patient baseline
characteristics were noted between treatment groups, except in
response to 1 mBPI-SF question; patients in the valdecoxib group
reported significantly greater interference in relations with
other people due to pain than did those in the placebo group (P
= 0.048). Changes from baseline in low back pain intensity were
significantly greater in valdecoxib-treated patients at each assessment
(all, P < 0.001 vs placebo). Pain scores on the mBPI-SF indicated
significantly greater pain relief with valdecoxib at each assessment
(all, P < or = 0.014 vs placebo). Improvements in mean Roland-Morris
Disability Questionnaire score with valdecoxib were significantly
greater than with placebo at each assessment (all, P < or =
0.003). Although the overall incidence of adverse events (AEs)
was significantly higher among patients receiving valdecoxib than
those receiving placebo (35.1% vs 24.1%, respectively; P = 0.042),
no significant differences were found between groups for the incidence
of any individual AE. Most AEs (89% [77/87 total events]) were
mild or moderate in severity. CONCLUSIONS: In this study of patients
with chronic low back pain, valdecoxib 40 mg/d provided rapid
relief (within 1 week) and consistent relief (over 4 weeks). In
addition, significant improvement in function and decreased disability
were found with valdecoxib compared with placebo.
Pain. 2004 Oct;111(3):286-96.
Efficacy and safety of valdecoxib for treatment of osteoarthritis
and rheumatoid arthritis: systematic review of randomised controlled
trials.
Edwards JE, McQuay HJ, Moore RA.
Nuffield Department of Anaesthetics, University of Oxford, Oxford
Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ,
UK.
Our objective was to determine the efficacy and safety of valdecoxib
(a cyclo-oxygenase 2 inhibitor) in the treatment of arthritis.
Randomised, controlled trials comparing 10 or 20mg valdecoxib
with placebo or non-steroidal anti-inflammatory drugs (NSAIDs)
in patients with active osteoarthritis or rheumatoid arthritis.
The manufacturer provided clinical trial reports. Data were combined
through meta-analysis. Main outcomes were patient global rating
of arthritis, arthritis pain, Western Ontario and McMaster Universities
indices for osteoarthritis, American College of Rheumatology indices
for rheumatoid arthritis, discontinuation, endoscopic ulcers,
clinically significant upper gastrointestinal or renal events.
Nine trials (five in osteoarthritis, four in rheumatoid arthritis)
were included with 5726 patients. Overall, valdecoxib 10 and 20mg
were superior to placebo and equivalent in efficacy to maximum
daily doses of NSAIDs. Significantly fewer discontinuations because
of gastrointestinal adverse events (4% versus 8%), or endoscopic
ulcers of 3mm or more (5% versus 13%) occurred with valdecoxib
compared with NSAIDs. Clinically significant upper gastrointestinal
events occurred in 2/2733 (0.1%) with valdecoxib compared with
8/1846 (0.4%) with NSAIDs. Rates of clinically significant renal
events were the same (2-3%) for valdecoxib and NSAIDs. At an appropriate
dose valdecoxib was as effective as NSAIDs in osteoarthritis and
rheumatoid arthritis. There were fewer gastrointestinal adverse
event withdrawals and endoscopically detected ulcers. Convincing
evidence of reduced major gastrointestinal adverse events could
not be addressed by the trials.
Aliment Pharmacol Ther. 2004 Sep 1;20(5):527-38.
Reduced incidence of upper gastrointestinal ulcer complications
with the COX-2 selective inhibitor, valdecoxib.
Goldstein JL, Eisen GM, Agrawal N, Stenson WF, Kent JD, Verburg
KM.
University of Illinois at Chicago, Chicago, IL 60612, USA.
AIM: In a predefined analysis, data were pooled from eight blinded,
randomized, controlled trials, and separately from three long-term,
open-label trials to determine the rate of upper gastrointestinal
ulcer complications with the cyclo-oxygenase-2 selective inhibitor,
valdecoxib, vs. non-selective non-steroidal anti-inflammatory
drugs. METHODS: In randomized, controlled trials, 7434 osteoarthritis
and rheumatoid arthritis patients received placebo (n = 973),
valdecoxib 5-80 mg daily (n = 4362), or a non-selective non-steroidal
anti-inflammatory drug (naproxen, ibuprofen or diclofenac; n =
2099) for 12-26 weeks. In long-term, open-label trials, 2871 patients
received valdecoxib 10-80 mg daily for up to 1 year. All potential
events were reviewed by a blinded, independent review committee
based on a priori definitions of ulcer complications (perforations,
obstructions, bleeds). RESULTS: In randomized, controlled trials,
19 of 955 potential events were adjudicated to be ulcer complications.
Valdecoxib was associated with a significantly lower ulcer complication
rate than non-selective non-steroidal anti-inflammatory drugs
(0.68% vs. 1.96%, all patients; 0.29% vs. 2.08%, non-aspirin users;
P < 0.05). In long-term, open-label trials, seven of 310 potential
events were adjudicated to be ulcer complications; the annualized
incidence for valdecoxib was 0.39% (seven of 1791 patient-years)
for all patients and 0.2% (three of 1472 patient-years) for non-aspirin
users. CONCLUSIONS: Valdecoxib, including above recommended doses,
is associated with a significantly lower rate of upper gastrointestinal
ulcer complications than therapeutic doses of non-selective non-steroidal
anti-inflammatory drugs.
Am J Ther. 2004 Jul-Aug;11(4):244-50.
Effects of the cyclooxygenase-2 specific inhibitor valdecoxib
versus nonsteroidal antiinflammatory agents and placebo on cardiovascular
thrombotic events in patients with arthritis.
White WB, Strand V, Roberts R, Whelton A.
Division of Hypertension and Clinical Pharmacology, Department
of Medicine, University of Connecticut School of Medicine, 263
Farmington Avenue, Farmington, CT 06030-3940, USA.
There have been concerns that the risk of cardiovascular thrombotic
events may be higher with cyclooxygenase (COX)-2-specific inhibitors
than nonselective nonsteroidal antiinflammatory drugs (NSAIDs).
We evaluated cardiovascular event data for valdecoxib, a new COX-2-specific
inhibitor in approximately 8000 patients with osteoarthritis and
rheumatoid arthritis treated with this agent in randomized clinical
trials. The incidence of cardiovascular thrombotic events (cardiac,
cerebrovascular and peripheral vascular, or arterial thrombotic)
was determined by analyzing pooled valdecoxib (10-80 mg daily),
nonselective NSAID (diclofenac 75 mg bid, ibuprofen 800 mg tid,
or naproxen 500 mg bid) and placebo data from 10 randomized osteoarthritis
and rheumatoid arthritis trials that were 6-52 weeks in duration.
The incidence rates of events were determined in all patients
(n = 7934) and in users of low-dose (< or =325 mg daily) aspirin
(n = 1051) and nonusers of aspirin (n = 6883). Crude and exposure-adjusted
incidences of thrombotic events were similar for valdecoxib, NSAIDs,
and placebo. The risk of serious thrombotic events was also similar
for each valdecoxib dose. Thrombotic risk was consistently higher
for users of aspirin users than nonusers of aspirin (placebo,
1.4% vs. 0%; valdecoxib, 1.7% vs. 0.2%; NSAIDs, 1.9% vs. 0.5%).
The rates of events in users of aspirin were similar for all 3
treatment groups and across valdecoxib doses. Short- and intermediate-term
treatment with therapeutic (10 or 20 mg daily) and supratherapeutic
(40 or 80 mg daily) valdecoxib doses was not associated with an
increased incidence of thrombotic events relative to nonselective
NSAIDs or placebo in osteoarthritis and rheumatoid arthritis patients
in controlled clinical trials.
J Indian Med Assoc. 2003 Dec;101(12):764, 766,
727.
Evaluation of the efficacy, safety and tolerability of valdecoxib
gel (1%) in adult patients with painful inflammatory joint disease.
Jagtap SA, Chincholi S, Taneja PK, Ismail ND, Ram S, Sarvagod
SB, Dongre N, Desai A.
Sir JJ Group of Hospitals and Grant Medical College, Mumbai 400008.
Valdecoxib, a COX-2 inhibitor, has recently been introduced as
a gel formulation. The present study was conducted to evaluate
the efficacy, safety and tolerability of valdecoxib gel in adult
patients with painful inflammatory joint conditions. The present
study was a 10-day prospective, open, multicentric (6 centres)
trial. Patients with clinical and radiological diagnosis of painful
inflammatory joint conditions were treated with valdecoxib gel
(1%). Efficacy was assessed by visual analogue scale (VAS), patient's
and physician's global assessment of pain relief. Grading of associated
clinical manifestations such as stiffness, swelling, tenderness
and restriction of mobility was done. Tolerability and safety
was assessed by physical examination, laboratory parameters and
evaluation of adverse events. There was a statistically significant
decrease in the mean pain visual analogue score (p<0.05). Onset
of pain relief was within 15 minutes. There was a reduction of
58.8%, 57.2%, 65.4% and 60.2% in mean scores of stiffness, swelling,
tenderness and mobility respectively from the baseline which was
statistically significant. The laboratory values were within normal
limits. The drug was well tolerated. There was no report of any
hypersensitivity reaction. This study confirms that valdecoxib
gel (1%) is an effective and safe option for the management of
painful inflammatory joint conditions.
Rev Med Liege. 2004 Apr;59(4):251-4.
[Valdecoxib (Bextra)] [Article in French]
Scheen AJ, Malaise M.
Universite de Liege.
Valdecoxib (Bextra tablets of 10 mg and 20 mg) is a new non steroidal
antiinflammatory drug (NSAID) that selectively inhibits COX-2
isoform of cyclo-oxygenase. It is indicated for the symptomatic
treatment of osteoarthritis or rheumatoid arthritis (10 to 20
mg once a day) and for the treatment of primary dysmenorrhea (40
mg once a day). Valdecoxib is as efficacious as conventional non-COX-2
selective NSAIDs, but offers the advantage of a much better gastrointestinal
tolerance. Valdecoxib has a prodrug that can be administered intravenously
or intramuscularly (parecoxib, Dynastat) and has been developed
for the short-term treatment of postsurgical pain.
Drugs. 2004;64(11):1231-61.
Valdecoxib: a review of its use in the management of osteoarthritis,
rheumatoid arthritis, dysmenorrhoea and acute pain.
Fenton C, Keating GM, Wagstaff AJ.
Adis International Limited, Auckland, New Zealand.
Valdecoxib is an orally administered, highly selective cyclo-oxygenase
(COX)-2 inhibitor with anti-inflammatory and analgesic properties.
In well designed trials, valdecoxib demonstrated efficacy versus
placebo in patients with osteoarthritis (OA), rheumatoid arthritis
(RA), primary dysmenorrhoea and postoperative pain. Initial results
in patients with migraine headache were promising. The efficacy
of valdecoxib appears dose dependent up to 40 mg/day. Valdecoxib
10 mg/day was as effective as naproxen and rofecoxib in improving
signs and symptoms of OA. The American College of Rheumatology
20% response rate was similar in recipients of valdecoxib, naproxen
and diclofenac in patients with RA. In patients with dysmenorrhoea,
valdecoxib 20 or 40 mg up to twice daily provided as effective
pain relief as naproxen sodium 550 mg twice daily. In acute post-surgical
pain, single-dose valdecoxib 40 mg had a rapid onset of action,
provided similar analgesia to oxycodone 10 mg plus paracetamol
(acetaminophen) 1000 mg and provided a longer time to rescue medication
than rofecoxib or oxycodone/paracetamol after oral surgery. Pre-emptive
administration of valdecoxib 10-80 mg was particularly effective
in dental pain. Valdecoxib had opioid-sparing effects after hip
or knee arthroplasty and reduced pain after laparoscopic cholecystectomy.
Valdecoxib is generally well tolerated. The incidence of gastroduodenal
ulcers was generally lower than with nonselective NSAIDs (i.e.
NSAIDs not specifically developed as selective COX-2 inhibitors).
With concomitant aspirin, the ulcer rate in valdecoxib recipients
increased significantly, but was still lower than that in recipients
of aspirin plus nonselective NSAIDs. In conclusion, valdecoxib,
a COX-2-selective inhibitor, is as efficacious in pain relief
as nonselective NSAIDs, with better gastrointestinal tolerability.
It was as effective in RA, OA and primary dysmenorrhoea (the approved
indications) as nonselective NSAIDs and as effective as rofecoxib
in RA flare. In acute post-surgical pain, valdecoxib provided
similar pain relief to oxycodone/paracetamol, had a long duration
of action, a rapid onset of analgesia and was opioid-sparing.
Valdecoxib provides a valuable alternative in the treatment of
chronic arthritis pain and acute pain.
J Clin Pharmacol. 2003 Sep;43(9):974-82.
Valdecoxib, a COX-2-specific inhibitor, does not affect cardiac
repolarization.
Sarapa N, Britto MR, Cotton B, Cox SR, Francom SF, Jin N, Polasek
ED, Sainati SM, Crosby-Sessoms SL, Fleishaker JC.
Department of Clinical Pharmacology, Pharmacia Corporation, 5200
Old Orchard Road, Skokie, IL 60077, USA.
This double-blind, four-way crossover study assessed the effect
of valdecoxib on the QTc interval duration in 25 male and 9 female
healthy adults. Subjects received placebo or 40 mg, 80 mg, or
120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained
for 24 hours before the first treatment (baseline) and on the
5th day of each treatment. The study was statistically powered
to detect a difference of > or = 5.6 ms in the average daily
QTc change from baseline and a > or = 7.8-ms difference in
the average maximal daily change from baseline. No QTc prolongation
versus placebo (Fridericia's or Bazett's correction) was observed
for any valdecoxib dose. A 22% greater than proportional increase
in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose
range, supporting the conclusiveness of the negative QTc risk
assessment even at supratherapeutic doses (up to three times the
maximum recommended dose of 40 mg per day) and concentrations.
In conclusion, repeated administration of doses up to 120 mg valdecoxib
had no effect on cardiac repolarization in healthy volunteers,
suggesting that chronic administration of valdecoxib to patients
would not increase the risk from cardiac arrhythmia associated
with QT prolongation.
Clin Ther. 2003 Mar;25(3):817-51.
Valdecoxib: a review.
Chavez ML, DeKorte CJ.
Pharmacy Practice Department, College of Pharmacy, Midwestern
University-Glendale, Glendale, Arizona 85308, USA.
BACKGROUND: Traditional nonsteroidal anti-inflammatory drugs (NSAIDs)
such as diclofenac, ibuprofen, naproxen, and related agents are
nonselective inhibitors of both cyclooxygenase-1 (COX-1) and COX-2,
which catalyze prostaglandin synthesis. This inhibition accounts
not only for the analgesic, anti-inflammatory, and antipyretic
effects of these agents, but also for side effects such as gastric
mucosal damage and renal toxicity. Substantial evidence suggests
that sparing COX-1 is advantageous for gastric safety. OBJECTIVE:
This article reviews available information on the new COX-2-selective
inhibitor valdecoxib, including its clinical pharmacology, pharmacokinetics,
adverse effects, potential drug interactions, and contraindications
and warnings. Results of clinical trials of efficacy and tolerability
are summarized. METHODS: Articles for inclusion in this review
were identified through searches of PubMed and MEDLINE (1966-December
2002) and International Pharmaceutical Abstracts (1970-December
2002). Search terms included valdecoxib, Bextra, COX-2-selective
inhibitors, coxibs, and selective cyclooxygenase inhibitors. The
reference lists of identified articles were reviewed for additional
publications. Product information was also obtained from the manufacturer
of valdecoxib. RESULTS: Fourteen clinical studies involving >
4000 patients have been conducted. Valdecoxib was significantly
more effective than placebo in the treatment of adult rheumatoid
arthritis, osteoarthritis, pain associated with primary dysmenorrhea,
and postoperative pain. Valdecoxib was comparable to naproxen
for the treatment of rheumatoid arthritis in 1 study and equivalent
to naproxen for the treatment of osteoarthritis in other studies.
Three studies found valdecoxib comparable to naproxen sodium for
the relief of moderate to severe pain due to primary dysmenorrhea,
and others found valdecoxib comparable to oxycodone plus acetaminophen
and significantly more effective than rofecoxib for the relief
of pain associated with dental surgery (P < 0.05). Four safety
studies and 2 reviews of clinical trials documented lower rates
of endoscopic gastroduodenal ulcer formation with valdecoxib compared
with ibuprofen, naproxen, and diclofenac (P < 0.001 to P <
0.05). Valdecoxib did not inhibit platelet function (bleeding
time and platelet aggregation) in healthy adults or in the elderly.
Due to the risk of potentially serious skin and allergic reactions,
patients who are allergic to sulfa-containing drugs should not
take valdecoxib. The drug should be discontinued immediately if
rash develops. CONCLUSIONS: In clinical trials, valdecoxib was
effective for the treatment of osteoarthritis, rheumatoid arthritis,
and moderate to severe pain associated with primary dysmenorrhea.
As with the other COX-2-selective inhibitors (celecoxib and rofecoxib),
valdecoxib appears to produce less gastrointestinal toxicity than
conventional nonselective NSAIDs, although some of the relevant
clinical studies have been published only as abstracts. Use of
valdecoxib should be reserved for patients at risk for NSAID-induced
gastrointestinal problems.
Aliment Pharmacol Ther. 2003 Jul 1;18(1):125-32.
A comparison of the upper gastrointestinal mucosal effects of
valdecoxib, naproxen and placebo in healthy elderly subjects.
Goldstein JL, Kivitz AJ, Verburg KM, Recker DP, Palmer RC, Kent
JD.
University of Illinois at Chicago, Chicago, IL 60612, USA.
BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2
specific inhibitors spare COX-1 at supratherapeutic doses and
therefore demonstrate improved gastrointestinal safety over nonspecific
nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical
practice, anti-inflammatory drugs are often used for short-term
treatment of pain. AIM: To compare the short-term upper gastrointestinal
mucosal effects of naproxen with the new COX-2 specific inhibitor,
valdecoxib, or placebo, in elderly subjects. METHODS: In this
multicentre, double-blind, randomized, study, elderly subjects
(65-76 years old), with a normal baseline esophagogastroduodenoscopy
(EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d.
dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n
= 62) for 6.5 days. Upper gastrointestinal mucosal injury was
evaluated post-treatment by EGD (day 7). RESULTS: Subjects receiving
naproxen (11/60, 18%) had significantly more gastroduodenal ulcers
post-treatment than those receiving placebo (2/61, 3%; P <
0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant
finding was observed for gastric ulcer rates. All treatments had
similar adverse event rates and clinical laboratory findings.
CONCLUSIONS: Valdecoxib, even at supratherapeutic doses, was associated
with an ulcer rate significantly lower than naproxen but similar
to placebo in healthy elderly subjects, despite the short duration
of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated
as placebo.
Rheumatology (Oxford). 2003 Oct;42(10):1207-15.
Valdecoxib is as effective as diclofenac in the management of
rheumatoid arthritis with a lower incidence of gastroduodenal
ulcers: results of a 26-week trial.
Pavelka K, Recker DP, Verburg KM.
Institute of Rheumatology, Prague, Czech Republic.
OBJECTIVE: To compare the efficacy and upper gastrointestinal
(GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac
75 mg slow release (SR) twice daily in treating rheumatoid arthritis
(RA). METHODS: Seven hundred and twenty-two patients with adult-onset
RA were enrolled into this 26-week, randomized, multicentre, double-blind,
parallel-group study (246 in the valdecoxib 20 mg daily arm, 237
in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75
mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per
day) was similar across all groups: 5.4% in the diclofenac group,
5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib
40 mg group. Efficacy was measured by the Patient's Assessment
of Arthritis Pain [visual analogue scale (VAS)] and the modified
Health Assessment Questionnaire (mHAQ) at baseline and at weeks
2, 6, 8, 12, 18 and 26 of treatment, or at early termination.
Upper GI safety was evaluated by endoscopy at the end of treatment,
which took place no more than 2 days after the last dose of study
medication or at early termination. RESULTS: Valdecoxib 20 and
40 mg daily were comparable to diclofenac 75 mg SR twice daily
in treating the signs and symptoms of RA. No significant differences
were observed between treatment groups with respect to mean changes
from baseline in the Patient's Assessment of Arthritis Pain (VAS)
or mHAQ. The incidence of gastroduodenal ulcers in patients receiving
valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was
significantly lower (P < 0.001) than in patients receiving
diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily
was also associated with significantly improved GI tolerability
(P = 0.035) compared with diclofenac. CONCLUSIONS: Single daily
doses of valdecoxib 20 and 40 mg provided efficacy comparable
to that of diclofenac, with a superior upper GI safety profile
in the long-term treatment of RA patients.
