ARTHRITIS
March 15, 2000

The New COX 2 Inhibitors

Until recently, the drugs used for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis (RA), were introduced either through clinical observations or as a result of a lucky guess. Since antiquity, for example, we observed that aspirin, the active ingredient in willow bark and other plant extracts, reduced pain and lowered fevers. Likewise, doctors treated RA patients with gold salts because it was believed that RA was caused by an organism similar to tuberculosis, and heavy metals, including gold, were used to treat TB.

Now, as scientists unravel the mysteries of the cellular and molecular mechanisms that cause these diseases, they also try to find which drugs would best affect these mechanisms. As a result, aspirin, indomethacin, gold salts, penicillamine and antimalarials, already in use for the treatment of RA, were each tested in the laboratory to determine their therapeutic effectiveness at this basic, molecular level. I call this Cinderella pharmacology -- the scientist has a glass slipper (effective drug) and proceeds to try it on every promising woman (possible cellular cause of the disease) that comes along.

COX Inhibition and Prostaglandins
In a recent major Cinderella advance, Dr. John Vane and his colleagues showed that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) inhibited the enzyme, cyclooxygenase (COX) and that this inhibition was responsible for their antiinflammatory properties.

We now know that COX controls the production of prostaglandin (a hormone) from arachidonic acid, a precursor molecule found in all cell membranes and that prostaglandin works as a messenger, telling cells to "rev up" their inflammatory response. As a result of this revving up, blood vessels expand, their walls become "leaky" and pain receptors are put on high alert.

As a consequence of Dr. Vane's research, pharmaceutical companies began screening compounds for their ability to inhibit cyclooxygenase in the laboratory on the assumption that they would thus be able to predict a compound's antiinflammatory action. Through these efforts, pharmaceutical companies introduced many new NSAIDs that worked in the laboratory. Unfortunately, all of these drugs produced stomach irritation in many people -- especially the elderly, patients with a prior history of peptic ulcer and patients who were taking corticosteroids -- as well as other serious effects on blood clotting and kidney function, so most were abandoned.

There's Not One But Two
The search for better drugs continued and researchers found that there were really two different COX enzymes. They are referred to as cyclooxygenase 1 (COX 1) and cyclooxygenase 2 (COX 2).

While the molecular arrangement of COX 1 and COX 2 are 70% identical, they are the products of two different genes that reside on different chromosomes. COX 1 is a constitutive enzyme, that is, it's present in all cells, while COX 2 has to be induced -- another molecule ("modulator") is required to make it appear in certain cells, which is probably what happens in the so-called inflammatory response.

Further research showed that the two COX enzymes attach to different sites on the arachidonic acid. This important discovery allowed scientists to focus on ways to stop prostaglandin production by the infrequently present COX 2.

Do Selective COX 2 Inhibitors Produce Ulcers
The first of these selective COX 2 inhibitors, celocoxib (Celebrex®), was approved by the FDA for the treatment of osteoarthritis and rheumatoid arthritis. In addition, the drug will probably be used for the treatment of arthritic pain and for the treatment of other forms of chronic arthritis, including psoriatic arthritis and reactive arthritis.

A second selective COX 2 inhibitor, refocoxib (Vioxx®), was recently approved for the treatment of acute pain and for symptomatic treatment of osteoarthritis. Its use in the treatment of rheumatoid arthritis is still pending, though many rheumatologists are already using it for this indication.

The primary advantage of these selective COX 2 inhibitors is that they cause very few cases of stomach ulceration. In double blind prospective studies, the prevalence of significant gastric ulcerations was the same with celocoxib and refocoxib as it was with placebo (approximately 5%). This compares favorably with the 15-20% incidence seen in those patients who received traditional NSAIDs.

The incidence, however, of gastric ulceration in patients who are also taking steroids or in patients with a recent history of gastric or duodenal ulcers has not been studied with these newer agents.

Other Side Effects
Both celocoxib and refocoxib have no effect on platelets or bleeding time. Therefore, these drugs do not have to be discontinued prior to elective surgery. The COX 2 enzyme is present in some cancer cells and has been demonstrated in the blood tissue surrounding adenomatous premalignant polyps of the colon. It is, therefore, reasonable to expect that the selective COX 2 inhibitors will be as effective as the traditional nonselective NSAIDs in suppressing the conversion of a colonic polyp to cancer.

Celocoxib and Rofecoxib
Celocoxib is rapidly and completely absorbed following oral ingestion, reaching a peak blood level after three hours. The absorption is not affected significantly by the presence of food. After ten days, a steady blood level is achieved. The drug is metabolized by the liver to inactive metabolites, which are excreted both in the gut and in the urine. The drug's break down is slowed by fluconazole (used in the treatment of severe fungal infections), which is metabolized by the same enzyme. There is no interaction between celocoxib and coumarin, an anticoagulant, or the oral hypoglycemic agents used in the treatment of diabetes.

Because celocoxib contains a sulfa molecule, it should be given with caution to patients with a history of sulfa allergy. The drug is not recommended during the third trimester of pregnancy because it may cause congenital heart damage to the fetus. The effect on early pregnancy has not been studied but, in animals, the drug does not appear to cause genetic damage.

Rofecoxib, like celecoxib, is completely absorbed when taken by mouth. The absorption is not influenced by food in the stomach. Like celecoxib, rofecoxib is metabolized in the liver but by a slightly different mechanism and may have some minor metabolic interactions with methotrexate, the chemotherapeutic agent also used to treat rheumatoid arthritis.

Dosage
The dose of celocoxib recommended for osteoarthritis is 100 mg twice a day or 200 mg once a day. In rheumatoid arthritis, the recommended dose is 100 to 200 mg twice a day. Higher doses are not accompanied by greater antiinflammatory efficacy. The dose of rofecoxib is 12.5 mg or 25 mg taken once daily.

The cost of these drugs is comparable to the cost of the newer NSAIDs. The most common side effect associated with celocoxib and refocoxib, so far, has been the development of indigestion (dyspepsia). There is no correlation between the development of dyspepsia and the incidence of gastric ulcers or significant blood loss.

Conclusion
While it is likely that several more selective inhibitors of COX 2 will be developed, some of which may be targeted to enzymes in specific cells, it is still apparent that the first generation of these drugs represents a significant step forward in antiinflammatory therapy.
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