Disease relevance of Valdecoxib

• Similarly, valdecoxib 5 and 10 mg/day were as effective for osteoarthritis of the hip as naproxen 500mg twice daily [1].
• A similar reduction in hyperalgesia and allodynia was noted after twice daily administration of another COX-2 inhibitor, valdecoxib, whilst a single acute administration of either drug on day 20, produced no anti-nociceptive activity [2].
• Valdecoxib is effective in single doses of up to 40 mg for the alleviation of acute menstrual pain and has a rapid onset of action (within 30 min) and a long duration of analgesia (up to 24 h) [3].
• CONCLUSIONS: Preoperative orally administered valdecoxib provides well-tolerated and effective analgesia for mild to moderate postoperative pain [4].
• 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) [5].

Psychiatry related information on Valdecoxib

• Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation [6].

High impact information on Valdecoxib

• METHODS: A systematic search of Medline and US Food and Drug Administration electronic databases was performed to identify randomized, placebo-controlled clinical trials of coxibs (etoricoxib, celecoxib, rofecoxib, valdecoxib) in patients with hip and/or knee OA [7].
• COX-2-selective inhibitor valdecoxib induces severe allergic skin reactions [8].
• Characterization of celecoxib and valdecoxib binding to cyclooxygenase [9].
• METHODS: Sprague-Dawley rats were randomized to a 3-day oral treatment with ATV 10 mg/kg, valdecoxib, a selective COX2 inhibitor (VAL) 3 mg/kg, ATV+VAL or water alone [10].
• Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials [11].

Chemical compound and disease context of Valdecoxib

• In the first 2 years of marketing the reporting rate for Stevens-Johnson syndrome/toxic epidermal necrolysis with valdecoxib was 49 cases per million person-years of use, 6 cases per million person-years for celecoxib and 3 cases per million person-years for rofecoxib [12].
• 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%) [13].
• Clinical trials have demonstrated the efficacy and safety of celecoxib and rofecoxib for postoperative pain and for preemptive analgesia, and newer agents such as valdecoxib and etoricoxib also have demonstrated efficacy in these settings [14].
• 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) [15].
• These findings suggest that preoperative administration of parecoxib sodium, the injectable prodrug of the cyclooxygenase-2 specific inhibitor valdecoxib, is effective, safe, and well tolerated for treating postoperative pain [16].

Biological context of Valdecoxib

• In contrast to three nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), valdecoxib 40mg twice daily did not cause significant changes in platelet function and bleeding times [1].
• When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder [17].
• This study evaluated the analgesic efficacy, dose dependency, duration of action, and safety of the cyclooxygenase-2 specific inhibitor, valdecoxib, administered before oral or orthopedic surgery [4].
• BACKGROUND: Parecoxib, a cyclooxygenase-2-specific inhibitor with intended perioperative analgesic and antiinflammatory use, is a parenterally administered inactive prodrug undergoing rapid hydrolysis in vivo to the active cyclooxygenase-2 inhibitor valdecoxib [18].
• The pharmacokinetics and metabolism of valdecoxib, a potent cyclooxygenase-2 selective inhibitor, were investigated in mice [19].

Anatomical context of Valdecoxib

• In a highly sensitive assay for COX-1 with U937 microsomes where the arachidonic acid concentration was lowered to 0.1 microM, IC(50) values of 12, 2, 0.25, and 0.05 microM were obtained for etoricoxib, rofecoxib, valdecoxib, and celecoxib, respectively [20].
• STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled study compared the efficacy and upper gastrointestinal tract safety of valdecoxib at dosages of 5, 10, and 20 mg once daily with placebo and naproxen at the dosage of 500 mg twice daily [21].
• Absorption of valdecoxib was excellent since the recovery of unchanged valdecoxib in feces was <1% of the administered dose [22].
• Rofecoxib 50 mg and valdecoxib 20 or 40 mg in adults and adolescents with postoperative pain after third molar extraction: Results of two randomized, double-blind, placebo-controlled, single-dose studies [23].
• OBJECTIVE: The aim of this study was to compare the effects of valdecoxib 20 mg BID and naproxen 500 mg BID, administered for 6.5 days, on the upper gastrointestinal (UGI) mucosa of healthy older subjects (aged 65-75 years) as assessed by UGI endoscopy [24].

Associations of Valdecoxib with other chemical compounds

• Parecoxib (parecoxib sodium) is an injectable pro drug of valdecoxib, which is a potent and selective inhibitor of cyclo-oxygenase-2 [25].
• Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1 [17].
• In patients with rheumatoid arthritis, valdecoxib 10, 20 or 40 mg/day was significantly more effective than placebo, and similar in efficacy to naproxen 500mg twice daily; there were no significant differences in efficacy between the three dosages of valdecoxib [1].
• When costs of gastrointestinal SAEs were averaged over the entire population, valdecoxib was suggested to have lower total costs per patient compared with diclofenac (cost savings of 115 British pounds per patient), mainly resulting from significant savings in hospitalization costs (76.49 British pounds per patient) [26].
• Using the ratio of IC(50) values (COX-1/COX-2), the selectivity ratio for the inhibition of COX-2 by etoricoxib in the human whole blood assay was 106, compared with values of 35, 30, 7.6, 7.3, 2.4, and 2.0 for rofecoxib, valdecoxib, celecoxib, nimesulide, etodolac, and meloxicam, respectively [20].

Gene context of Valdecoxib

• Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2 [27].
• Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM) [27].
• It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates [28].
• Both parecoxib and valdecoxib inhibit human cytochrome P450 2C9 (CYP2C9) activity in vitro [18].
• By contrast, other selective (celecoxib, valdecoxib, meloxicam) and non-selective COX inhibitors (ibuprofen, naproxen, diclofenac) had no significant effect on LDL oxidation rates or plasma ORAC values, even at suprapharmacologic levels [29].

Analytical, diagnostic and therapeutic context of Valdecoxib

• Valdecoxib 20 or 40mg administered 1 to 3 hours before and 12, 24 and 36 hours after hip arthroplasty provided significantly better analgesia than placebo, and significantly reduced the amount of morphine taken by patients [1].
• Valdecoxib had opioid-sparing effects after hip or knee arthroplasty and reduced pain after laparoscopic cholecystectomy [30].
• In particular, the incidence of hospitalization and number of hospital days for gastrointestinal SAEs was lower in the valdecoxib group [26].
• Meta-analysis: upper gastrointestinal tolerability of valdecoxib, a cyclooxygenase-2-specific inhibitor, compared with nonspecific nonsteroidal anti-inflammatory drugs among patients with osteoarthritis and rheumatoid arthritis [31].
• In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg) [27].

References