Gastrointestinal Ulceration

Despite the COX-1-sparing property of the coxibs, concern remains as to whether they have the same potential to cause gastrointestinal (GI) ulcers as conventional week, randomized, placebo-controlled study, Kivitz et al. compared the risk of GI ulceration with valdecoxib 5, 10, and 20 mg four times a day (QD); naproxen 500 mg BID; and placebo in approximately 1,000 patients with OA. Patients underwent an endoscopy at pre- and post-treatment to assess the presence of an ulcer. Results showed that patients taking naproxen 10% (P< 0.05) developed significantly more GI ulcers than those taking placebo (4%) or valdecoxib 5 mg or 10 mg (3°% (P< 0.05) vs. 3°% (P<0.01), respectively). Overall, valde-coxib had a safer profile with respect to GI safety and tolerability.

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Valdecoxib is metabolized via the cytochrome P(CYP)-450 system, pre dominately 3A4 and 2C9, as well as non-P450 systems, including approximately 20% glucuronidation. Valdecoxib has one metabolite that is excreted in the urine, but it has not been shown to have significant activity or to contribute to the drug’s profile. Because valdecoxib is a substrate for the 3A4 enzyme, precaution should be taken when coadministering with inhibitors or inducers of this enzyme system. When potent inhibitors of the 3A4 system (i.e., fluconazole and ketocona-zole) where administered with a single dose of valdecoxib 20 mg, plasma concentrations increased to 62% with fluconazole and 38% with ketoconazole. Although they have not been fully established, similar effects can be seen with other 3A4 inhibitors such as ery-thromycin, itraconazole, and ritonavir. Despite the lack of clinical studies, this pharmacokinetic drug interaction should be taken into consideration when coad-ministering valdecoxib with 3A4 inducers such as carbamazepine, phenobarbital, phenytoin and rifampin as well. Patients taking valdecoxib with anticonvulsants should be monitored appropriately when initiating or discontinuing therapy.

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Valdecoxib is a 4-[5-methyl-3-phenylisox-azol-4-yl]-benzenesulfonamide that works by selectively inhibiting the cyclooxygenase-2 enzyme. The process begins with a stimulus, either inflammatory or physiological, causing the release of arachidondic acid from cell membrane phospholipids. Arachidonic acid is converted to prostaglandins (PG) through the enzyme prostaglandin G/H synthase, also known as cyclooxygenase (COX) or hydroperoxidase (HOX), as seen in Figure 1. There are two types of COX enzymes that traditional NSAIDs inhibit: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Currently, there are no medications that selectively inhibit the activity of the HOX enzyme. The COX-1 enzyme is expressed in most body tissues (i.e., stomach, kidneys, platelets, and intestines) where it produces prostaglandins for physiological regulation of the body, or homeostatis. This includes gastrointestinal cytoprotection, maintenance of normal renal function, and platelet aggregation. Consequently, NSAIDs, which block the COX-1 enzyme, can cause gastrointestinal irritation and injury, antiplatelet effects and compromised renal function. By comparison, the COX-2 enzyme is expressed in lower levels at baseline in these tissues and are shown to be present in the brain, bones, female reproductive tract, and kidneys, and tends to be expressed in higher levels during an inflammatory process. With the use of the selective COX-2 inhibitors (or COX-1-sparing NSAID), patients can receive the same anti-inflammatory and analgesic effects as the traditional NSAIDs, sparing the adverse effects seen with the inhibition of COX-1. Studies show that valdecoxib and the others in its class do not inhibit the COX-1 enzyme at therapeutic concentrations.

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Valdecoxib (Bextra, Pharmacia) is the newest addition to the class of cyclooxygenase-2 inhibitors, which also includes celecoxib (Celebrex drug, Pharmacia/Pfizer Inc.) and rofecoxib (Vioxx, Merck). Valdecoxib received FDA approval in November 2001 for treating the signs and symptoms of osteoarthritis (OA) and adult rheumatoid arthritis (RA) and the treatment of pain associated with menstrual cramping (primary dysmenorrhea), as shown in Table 1. Valdecoxib is not approved for use in the pediatric population (<18 years of age) and unlike the others in this class, valdecoxib is not indicated for the management of acute pain in adults (Table 2).

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