Key Terms: Cyclooxygenase, Cyclooxygenase 1.
Definition
Cyclooxygenase 2 inhibitors, also known as COX-2 inhibitors, are useful as pain and antiflammatory medications for cancer patients. COX-2 inhibitors are not better at stopping pain and inflammation than other non-steroidal anti-inflammatory drugs (NSAIDs), but are less likely to cause stomach ulcers and bleeding.
Purpose
Nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat pain and inflammation are relatively effective in controlling these symptoms but can cause serious side effects. These side effects include stomach ulcers, kidney problems, and increased likelihood of bleeding. Aspirin is the most serious offender, although other pain medications in the NSAID class of medication present similar problems. COX-2 inhibitors were developed as a type of pain medication less likely to cause stomach and bleeding problems than existing NSAID pain medications.
COX-2 inhibitors may also have future applications in cancer therapy. Recent research suggests that COX-2 is involved in the growth of cancerous tumors; therefore, COX-2 inhibitors may prove to be helpful in preventing or slowing the growth of certain types of cancer. One group of researchers in Taiwan reported in 2003 that celecoxib inhibits the growth of cell lines derived from mouth cancers, while another group in Arizona found that COX-2 inhibitors may be effective in slowing the growth of malignant melanoma.
Description
Cyclooxygenase is a chemical important for the normal functioning of the human body. Cyclooxygenase helps the stomach and kidneys to function normally, the platelets in the blood to function normally, and the brain to regulate body temperature and feel pain. Scientists have discovered that there are two distinct types of cyclooxygenase (abbreviated COX). These two types of COX are known as COX-1 and COX-2. COX-1 is needed to maintain the normal body functions of platelet aggregation, the regulation of blood flow in the kidney and stomach, and the regulation of gastric acid secretion in the stomach.
COX-2 is produced only when the body's tissues have been injured. COX-2 mediates inflammation, helps the nerves feel pain, and helps the brain regulate fever. A medication that inhibits COX-2 can suppress inflammation, relieve pain, and reduce fever. Inhibition of COX-1, on the other hand, results in bleeding and kidney and stomach toxicity.
The problem with many older pain medications is that they affect both COX-1 and COX-2, even though they provid benefit only through how they affect COX-2. That is why their long-term use may be associated with such side effects as stomach ulcers, decreased kidney function, and a tendency for excessive bleeding. COX-2 inhibitors inhibit COX-2 while exerting less effect on COX-1.
At the end of 2003, three COX-2 inhibitors were available by prescription in the United States. Celecoxib (brand name Celebrex) was the first to be made available, followed by rofecoxib (brand name Vioxx) and valdecoxib (brand name Bextra), which was approved by the Food and Drug Administration (FDA) in late 2001. In addition, the pharmaceutical company Novartis had hoped to secure FDA approval in 2003 for a fourth COX-2 inhibitor named lumiracoxib, to be sold under the brand name Prexige. The FDA requested more data, however, and as of 2004 lumiracoxib has not yet been approved for use in the United States.
The FDA's reluctance to approve lumiracoxib may have been prophetic, insofar as the agency issued a public health advisory in late September 2004 regarding the safety of rofecoxib. The FDA was concerned about reports that Vioxx increased patients' risks of heart attack or stroke. The manufacturer voluntarily removed the drug from the market on September 30, 2004.
Recommended Dosage
Celecoxib comes in 100 mg and 200 mg capsules that are taken orally either once or twice a day.
Valdecoxib is available in 10 and 20 mg tablets.
Precautions
Celecoxib should not be taken by patients with sulfonamide allergy. This medication should not be taken during the last few months of pregnancy.
Valdecoxib should not be taken during the last trimester of pregnancy. In addition, patients taking valdecoxib should tell their doctor if they are pregnant or might become pregnant during treatment with the drug.
Side Effects
Celecoxib has few side effects. A small number of patients report stomach upset and even fewer report abdominal pain. Other effects reported rarely with celecoxib include kidney problems, fluid retention, and retention of water in the tissues. The occurrence of ulcers in patients taking celecoxib is less frequent than for many other pain medications. However, the long-term safety of celecoxib has not been well-researched.
Valdecoxib has been reported to cause weight gain, skin rashes, nausea and abdominal pain, itching, yellowing of the skin, flu-like symptoms, or unusual bruising or bleeding in some patients.
Interactions
Celecoxib may affect the activities of warfarin, a medication that limits the ability of blood to clot. Celecoxib may also be involved in interactions with: furosemide, a diuretic; angiotensin-converting enzyme inhibitors (ACE inhibitors), medicines used for high blood pressure and some heart problems; lithium, a medication for bipolar disorder; and fluconazole, an antifungal medication. Celecoxib may be taken with any of the medicines mentioned above—however, the doctor should closely monitor these drug combinations. Because celecoxib is a relatively new medication, more remains to be learned about its potential to interact with other drugs.
Valdecoxib may interact with NSAIDs, aspirin, lithium, steroid medications, ACE inhibitors, blood thinners (anticoagulants), and diuretics. In general, patients should make sure that their doctor has a complete list of all medications that they take on a regular basis—including over-the-counter pain relievers—before taking any COX-2 inhibitor.
Resources
Periodicals
Foral, P. A., K. K. Nystrom, A. F. Wilson, and C. M. Christensen. " Gastrointestinal-Related Adverse Effects of COX-2 Inhibitors." Drugs Today (Barcelona) 39 (December 2003): 939–948.
Goulet, A. C., J. G. Einsphar, D. S. Alberts, et al. "Analysis of Cyclooxygenase 2 (COX-2) Expression During Malignant Melanoma Progression." Cancer Biology and Therapy 2 (November-December 2003): 713–718.
Yang, C. Y., C. L. Meng, C. L. Liao, and P. Y. Wong. "Regulation of Cell Growth by Selective COX-2 Inhibitors in Oral Carcinoma Cell Lines." Prostaglandins and Other Lipid Mediators 72 (November 2003): 115–130.
Organizations
United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA (463-6332).
Other
FDA press release, September 30, 2004. "FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product." FDA document P04-95.
—Bob Kirsch; Rebecca J. Frey, PhD
