Coxibs

Lumiracoxib, which has been approved in the UK but not by the FDA, has a phenyl acetic acid structure resembling diclofenac rather than the other coxibs... 

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

Highly selective COX-2 inhibitors - coxibs (rofecoxib, celecoxib, or less popular - valdecoxib, etoricoxib parecoxiband lumiracoxib) - were found to be well tolerated in a series of placebo-controlled clinical trials [8]. However, rofecoxib and valdecoxib have been withdrawn from the market because of an increased incidence... 

Patients with chronic idiopathic urticaria, who develop cutaneous reactions in response to aspirin, display certain similarities in eicosanoid profile with AIA. The mechanism of the reactions is often related to COX-1 inhibition [18]. Therefore, aspirin and all drugs that inhibit COX-1 should be avoided in patients who already have had cutaneous reactions to NSAID. Coxibs are usually well tolerated, although occasional adverse reactions have been reported [19, 20]. For treatment of the reactions, antihistamines are usually sufficient, but in more severe cases adrenaline and corticosteroids may be warranted. 

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Topol EJ. Arthritis medicines and cardiovascular events house of coxibs. JAMA 2005 293 366-368. 

Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001 345 433-442. 

There is, therefore, a need for original coxibs, and one might think to look into the medicinal flora of Asia and the Pacific, as an increasing body of evidence suggests the families Apocynaceae, Clusiaceae, Asteraceae, Polygonaceae, Lamiaceae, and Con-volvulaceae to elaborate ast sources of biomolecules which are able to inhibit the enzymatic activity of COX. 

Bombardier C, Laine L, Reidn A, et al. Comparison of upper gastrointestinal toxicity of rofe-coxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 2000 343 1520-8. 

COX-1 and COX-2 are the targets of the nonsteroidal anti-inflammatory drugs (NSAID, see Chapter 28). Indirectely the effect of these enzymes is also inhibited by corticosteroids (see also Chapter 26) through a decrease of the availibility of its substrate arachidonic acid by inhibition of phospholipase A2. Relatively new drugs, known as COX-2 selective inhibitors or coxibs (celecoxib, rofecoxib and others), are used as specific inhibitors of COX-2. 

The development of these drugs allowed the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. However, it was subsequently shown that both NSAIDs and Coxibs can raise the risk of myocardial infarction, when taken on a chronic basis for at least 18 months. In 2004 rofecoxib was taken off the market for this reason. 

Coxibs (COX-2 inhibitors NSAIDs with COX-1-sparing effect) ... 

NSAID Selective COX-2 inhibitors a. Coxibs (celecoxib, rofecoxib)... 

Laine L et al Serious lower gastrointestinal clinical events with non-selective NSAID or coxib use. Gastroenterology 2003 124 288. [PMID 12557133]... 

Highly selective COX-2 inhibitors (e.g. celecoxib, second and third generation of COX-2 inhibitors, sometimes called coxibs)... 

Chavez-Eng, C. M., Constanzer, M. L., and Matuszewski, B. K. (2000). Determination of rofe-coxib (MK-0966), a cyclooxygenase-2 inhibitor, in human plasma by high-performance liquid chromatography with tandem mass spectrometric detection. J. Chromatogr. B Biomed. Set Appl. 748 31-39. 

Konstam MA, Weir MR. Current perspective on the cardiovascular effects of coxibs. Cleve Clin J Med. 2002 69(suppl 1) SI47-SI52. 

Cyclooxygenase type 2 [COX-2] inhibitors -coxib Celecoxib Pain, inflammation (15)... 

Similarly, the sodium salt of the poorly soluble COX-2 inhibitor pare-coxib, parecoxib sodium (Dynastat ), was designed as a parenteral analgesic for the management of acute pain to improve solubility of the parent compound. On administration, parecoxib sodium is converted rapidly and essentially completely to the pharmacologically active... 

Sorbera, L., Leeson, P. A., Castaner, J., and Castaner, R. M. Valdecoxib and pare-coxib sodium. Drugs Future 26 133-140, 2001. 

The coxibs continue to be investigated to determine whether their effect on prostacyclin production could lead to a prothrombotic state. The frequency of other adverse effects approximates that of other NSAIDs. Celecoxib causes no more edema or renal effects than other members of the NSAID group, but edema and hypertension have been documented. 

Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs. The drug is popular in Europe and many other countries for most rheumatic diseases and has recently been approved for treatment of osteoarthritis in the USA. Its efficacy in this condition and rheumatoid arthritis is comparable to that of other NSAIDs. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, it appears that even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result... 

Rofecoxib, a furanose derivative, is a potent, selective COX-2 inhibitor (Table 36-1). In the USA, rofecoxib is approved for osteoarthritis and rheumatoid arthritis, and it also appears to be analgesic and antipyretic—in common with other NSAIDs. This drug does not inhibit platelet aggregation and appears to have little effect on gastric mucosal prostaglandins or lower gastrointestinal tract permeability. At high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. 

Valdecoxib, a diaryl-substituted isoxazole, is a new highly selective COX-2 inhibitor. Pharmacokinetic characteristics and dosage in arthritis are set forth in Table 36-1. In primary dysmenorrhea, dosage is 20 mg twice daily, and the drug is as effective as nonselective NSAIDs for this indication. Gastrointestinal and other toxicities are similar to those of the other coxibs. Valdecoxib has no effect on platelet aggregation or bleeding time. Serious reactions have been reported in sulfonamide-sensitive individuals. 

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