Clinical use and pharmacological properties of selective COX-2 inhibitors

Abstract

Selective COX-2 inhibitors (coxibs) are approved for the relief of acute pain and symptoms of chronic inflammatory conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). They have similar pharmacological properties but a slightly improved gastrointestinal (GI) safety profile if compared to traditional nonsteroidal anti-inflammatory drugs (tNSAIDs). However, long-term use of coxibs can be associated with an increased risk for cardiovascular (CV) adverse events (AEs). For this reason, two coxibs were withdrawn from the market. Currently celecoxib, etoricoxib, and lumiracoxib are used. These three coxibs differ in their chemical structure and selectivity for COX-2, which might explain some of their pharmacological features. Following oral administration, the less lipophilic celecoxib has a lower bioavailability (20-40%) than the other two coxibs (74-100%). All are eliminated by hepatic metabolism involving mainly CYP2C9 (celecoxib, lumiracoxib) and CYP3A4 (etoricoxib). Elimination half-life varies from 5 to 8 h (lumiracoxib), 11 to 16 h (celecoxib) and 19 to 32 h (etoricoxib). In patients with liver disease, plasma levels of celecoxib and etoricoxib are increased about two-fold. Clinical efficacies of the coxibs are comparable to tNSAIDs. There is an ongoing discussion about whether the slightly better GI tolerability (which is lost if acetylsalicylic acid is coadministered) of the coxibs is offset by their elevated risks for CV AEs (also seen with tNSAIDs other than naproxen), which apparently increase with dose and duration of exposure. In addition, the higher costs for coxibs (if compared to tNSAIDs, even when a "gastroprotective" proton pump inhibitor is coadministered) should be taken into consideration, if a coxib will be selected for certain patients with a high risk for GI complications. For such treatment, the lowest effective dose should be used for a limited time. Monitoring of kidney function and blood pressure appears advisable. It is hoped that further controlled studies can better define the therapeutic place of the coxibs.

Influence of Oleic Acid on the Rheology and in Vitro Release of Lumiracoxib from Poloxamer Gels

“…Assignments of chemical shifts obtained by analyzing the carbon and hydrogen NMR spectra are described in Table 2. The identity of the compound was confirmed by NMR spectra of carbon and hydrogen and infrared spectroscopy (data not shown) and the results are in agreement with the literature (10,43). In addition, these results suggest the absence of contaminating substances, which confirm both the purity of the extracted drug and the effectiveness of the extraction procedure.…”

“…Due to its chemical structure (Figure 1) and pharmacological properties, LM appears to be different from other COX-2 inhibitors (1). When administered orally, this compound produces gastrointestinal benefits in patients with osteoarthritis, who show decreased severe gastrointestinal ulcer complications by more than 70%, compared with treatments with ibuprofen and naproxen (9)(10).…”

Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model

“…(Chaput and Tremblay, 2010). Additional drugs withdrawn from the market for cardiovascular toxicities and concerns include: rotecoxib (used to relieve acute pain and symptoms of chronic inflammation, removed from market in 2005) and valdecoxib (used to relieve acute pain and symptoms of chronic inflammation, removed from market in 2005) (Shi and Klotz, 2008). Toxicity screening identifies drug candidates that exhibit predictable/intrinsic drug-induced liver injury.…”

Nitrooxymethyl‐Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

“…These products, called Coxibs, are characterized by reducing prostaglandin (PG)-dependent inflammation, while maintaining protective gastric PG synthesis [2] [5] [6]. A number of them, Rofecoxib (1) [7], Celecoxib (2), Valdecoxib (3), Etoricoxib (4), and Lumiracoxib (5), were introduced into the market [8].…”

“…This cardiotoxicity is due to their capacity of reducing the biosynthesis of prostacycline (PGI 2 ) in vivo, with consequent tipping of prostanoid balance in favor of thrombogenic tromboxane [9 -11]. Because of their adverse cardiovascular effects, Rofecoxib and Valdecoxib were withdrawn from the market [8]. This removal decreased the interest in the selective COX-2 inhibitors and discouraged the pharmaceutical companies to develop further this kind of drugs.…”