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Individuals with osteoarthritis face an increased risk of cardiovascular (CV) disease compared with age-matched control subjects. Both conditions share some common risk factors (eg, age, obesity, and hypertension) and the consequences or treatment of osteoarthritis may increase CV risk by impairing physical activity and exacerbating CV risk factors. Nonsteroidal anti-inflammatory drugs may have prothrombotic and/or hypertensive effects and a negative impact on renal function, all of which contribute to the increased risk of CV disease associated with these agents. The magnitude of these effects differs between agents and is, in part, determined by the relative balance of cyclo-oxygenase-1 or cyclo-oxygenase-2 inhibition. To minimize risk of CV disease in patients with osteoarthritis taking nonsteroidal anti-inflammatory drugs, physicians need to 1) monitor blood pressure and the new appearance or exacerbation of edema; 2) encourage lifestyle changes/nonpharmacologic treatments for pain/risk factor management; 3) choose the lowest effective dose of appropriate drug therapy to achieve adequate pain relief while minimizing CV risk; 4) change nonsteroidal anti-inflammatory drugs as needed to one with lower propensity to aggravate CV risk; and 5) modulate antihypertensive therapy and diuretic management as needed to maintain target blood pressure and weight.

The incidence of gout and the clinical manifestation of hyperuricemia continue to rise. In addition to painful acute attacks, chronic gout can lead to the development of crystal arthropathy, tophi, and renal lithiasis, coincidental with declines in quality of life. As a greater appreciation for the associations between hyperuricemia, gout, and certain comorbidities, such as renal impairment and cardiovascular diseases, grows, so does the search for new therapeutic options to both alleviate the painful symptoms of acute gout attacks and reduce the underlying hyperuricemia. This manuscript reviews the pathophysiology of hyperuricemia and gout, and associated comorbidities, and then discusses traditional therapeutic options, newly available agents, and future targets for pharmacologic management.

Selective cyclooxygenase (COX)-2 inhibitors have been associated with an increased risk of thromboembolic cardiovascular (CV) events. Prior studies have found that rofecoxib has a destabilizing effect on blood pressure; however, whether this translates to an increased risk of thromboembolic CV events is unknown. The objective of this study was to evaluate risk of thromboembolic CV events among hypertensive and nonhypertensive patients treated with rofecoxib or celecoxib, nonselective nonsteroidal anti-inflammatory drugs (ns-NSAIDs), or no NSAIDs (nonusers). This was a retrospective cohort study of 31,743 adult arthritis patients enrolled in a Blue Cross/Blue Shield health insurance plan in the northeastern United States. The main outcome measure was incident acute myocardial infarction and stroke. A clinically significant channeling effect was observed where selective COX-2 inhibitor users had a more severe CV risk profile. Among normotensive patients, the hazard ratio (HR) of CV events for ns-NSAIDs, rofecoxib, or celecoxib versus nonusers was 0.91 (95% confidence interval, 0.68-1.21), 1.05 (0.61-1.80), and 1.19 (0.86-1.66), respectively. Among hypertensive patients, the risk of CV events for ns-NSAIDs users was not significantly different versus nonusers (HR = 1.21; 0.88-1.67). However, rofecoxib was associated with a significant 2-fold increase in CV risk versus nonusers of NSAIDs (HR = 2.16; 1.51-3.09), whereas celecoxib was not (HR = 1.18; 0.89-1.57). These data support the hypothesis that elevated CV risk is not a drug class effect of selective COX-2 inhibitors. That this effect was specific to hypertensive patients indicates that blood pressure destabilization is likely an important contributing mechanism.

Rofecoxib and celecoxib were the first cyclooxygenase-2 (COX-2)-specific inhibitors to be marketed as effective anti inflammatory agents. The results of several recent trials and a meta analysis of currently available studies all demonstrate a greater incidence of increased blood pressure, edema, and cardiovascular events in subjects treated with rofecoxib compared with celecoxib. As an approach to the assessment of molecular mechanisms that may contribute to these cardiorenal differences, this study investigated the inhibitory effects of celecoxib on renal carbonic anhydrase enzyme activity in human hypertensive subjects because in vitro enzyme studies demonstrate such an effect. Ten subjects with stable, treated hypertension were randomized to 1 of 3 treatment sequences, which included, in differing order, 200 mg celecoxib twice a day, 250 mg acetazolamide twice a day, or placebo twice a day. Whereas acetazolamide caused a bicarbonate diuresis and a hyperchloremic metabolic acidosis, celecoxib appeared to have no detectable effect on renal carbonic anhydrase or acid-base homeostasis. Thus, in this short-term study of human subjects, therapeutic doses of celecoxib did not appear to have a clinically significant inhibitory action on renal carbonic anhydrase.

Background Valdecoxib and its intravenous prodrug parecoxib are reported to increase thromboembolic risk after coronary artery bypass grafting. The authors conducted a randomized trial to examine their safety and analgesic efficacy in patients recovering from major noncardiac surgical procedures. Methods The trial was randomized and double-blind, with 10 days of treatment and 30 days of follow-up. Patients (n = 1,062) received either parenteral parecoxib for 3 days and oral valdecoxib for the rest of the treatment period or placebo medications throughout. The frequency of predefined adjudicated postrandomization adverse events, including cardiovascular thromboembolism, renal dysfunction, gastroduodenal ulceration, and wound-healing complications, was assessed in each group. Secondary efficacy endpoints included patients' pain ratings, opioid analgesic consumption (recorded as morphine equivalents), and reports of opioid-related adverse effects. Results Predefined adjudicated adverse events had similar frequencies among patients who received parecoxib and valdecoxib (2.7%) and placebo patients (3.2%) (P = 0.58), including cardiovascular thromboembolic events (1.0% in each group; P = 1.0). Placebo patients consumed more morphine equivalents (66.2 +/- 92.4 mg) than did patients receiving parecoxib and valdecoxib (43.2 +/- 65.7 mg) (P < 0.001). Placebo patients had higher mean pain ratings on each of study days 2-10 (P < 0.01) and reported more opioid-related symptom distress on days 2-6 (P < 0.01). Conclusions Parecoxib and valdecoxib are useful adjuncts to opioids for the treatment of postoperative pain in noncardiac surgical patients. Further study will be required to determine the safety profile of parecoxib and valdecoxib administered to patients with known atherosclerotic disease after noncardiac surgery.

Preexisting renal impairment is an all-encompassing risk factor for radiocontrast-associated nephrotoxicity. Renal impairment appears to be associated with the inadequate production of renal prostaglandins at the critical time of radiocontrast administration and for a variable time period afterward. We prospectively studied 130 patients with chronic renal insufficiency (serum creatinine > or =1.5 mg/dL) who were undergoing radiocontrast administration. Using a double-blind, randomized, prospective technique, patients were assigned to either placebo or one of three prostaglandin E1 (PGE1) treatment groups (10, 20, or 40 ng/kg/min). Infusion was started 60 +/- 30 minutes before the administration of radiocontrast and was continued for a total of 6 hours. In the placebo group, radiocontrast administration resulted in a mean increase (+/- SD) in serum creatinine of 0.72 +/- 1.15 mg/dL at 48 hours. This increase was less in each of the PGE1 treatment groups after 48 hours, with a significant difference between placebo and the 20 ng/kg/min PGE1 group (P = 0.01). Using baseline adjusted means, analysis of covariance with baseline serum creatinine as the covariable demonstrated significant differences between the placebo and 20 ng/kg/min PGE1 group (P = 0.03) and between the placebo and 10 ng/kg/min PGE1 group P = 0.047). In a subgroup analysis of the diabetic patients, the increase in serum creatinine was less pronounced in the three PGE1 groups versus the placebo group, and the 20 ng/kg/min PGE1 group had the most favorable outcome. The parenteral administration of PGE1 immediately before radiocontrast exposure and continued for a period of 5 to 5.5 hours significantly reduced the elevation of serum creatinine poststudy. The most effective of the three PGE1 dosing regimens was 20 ng/kg/min.

The novel cyclooxygenase- (COX)-2 inhibitor celecoxib is an effective treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. Conventional treatment for these debilitating conditions routinely involves the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), which are nonspecific inhibitors of COX-1 and COX-2. Numerous studies suggest that inhibition of renal prostaglandin synthesis by NSAIDs is deleterious to kidney function, particularly in high-risk patients. As celecoxib inhibits COX-2 and spares COX-1 at therapeutic doses, we hypothesized that it may offer an improved renal safety profile in patients at risk for NSAID-induced renal toxicity. This article represents a post hoc analysis of the renal safety of celecoxib, using the safety database generated during its clinical development program. This analysis includes data from more than 50 clinical studies involving more than 13,000 subjects. Most subjects were enrolled in randomized, controlled trials (of up to 12 weeks' duration); however, more than 5000 subjects received celecoxib for as long as 2 years in a long-term, open-label study at as much as twice the maximum recommended dosage. The overall incidence of renal adverse events after celecoxib was greater than that after placebo but similar to that after NSAIDs. The most common events reported after celecoxib, namely, peripheral edema (2.1%), hypertension (0.8%), and exacerbation of preexisting hypertension (0.6%), were not time- or dose-related. Peripheral edema was not associated with increased weight or blood pressure. Furthermore, there was no evidence of drug-drug interactions between celecoxib and concomitant angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, or diuretics. We conclude that celecoxib is well tolerated by patients who may be at risk for NSAID-induced renal toxicity, such as the elderly and those with hypertension or preexisting chronic heart disease.

In this double-blind, 6-week study comparing once-daily oral betaxolol and atenolol, the study design allowed the effects of simulated drug noncompliance to be examined. Overall similar blood pressure and heart rate responses were seen in 114 patients with mild-to-moderate hypertension. Similarly, there was no statistically significant difference in percentage of patients achieving goal diastolic blood pressure reductions at the end of 6 weeks of active therapy (betaxolol, 87%, 46/53; atenolol, 82%, 44/54), and safety results overall were similar. However, when patients randomly received placebo for two consecutive treatment days in either the fifth or sixth week of the study to simulate the effect of missing doses, magnitude and duration of effect on systolic blood pressure (p = 0.006), diastolic blood pressure (p = 0.02) and heart rate (p = 0.001) were significantly greater for betaxolol than atenolol as calculated from 28-h ambulatory blood pressure monitoring data. Although betaxolol and atenolol monotherapy are equally effective in controlling blood pressure when taken consistently, the blood pressure and heart rate response with betaxolol is significantly superior for at least 24 h after missing a dose, an important consideration related to patient noncompliance. These results are compatible with the different elimination half-lives of each drug.

Nephrotoxicity manifested by renal insufficiency is a well-known consequence of aminoglycoside administration in hospitalized patients. We report a case of aminoglycoside-induced nephrotoxicity in a young woman with cystic fibrosis that illustrates the classical presentation of nonoliguric renal failure and the risk factors that predispose to the development of aminoglycoside renal toxicity. The incidence of aminoglycoside nephrotoxicity in cystic fibrosis appears to be lower than that expected for a population exposed to prolonged and repetitive courses of therapy with these agents. Cystic fibrosis is a unique disease in which the pharmacokinetic profile of many drugs is abnormal. The pharmacokinetics of aminoglycosides in cystic fibrosis are characterized by an increased drug clearance and a larger volume of distribution; why cystic fibrosis patients should exhibit these abnormalities remains an enigma. If, in fact, patients with cystic fibrosis have a resistant phenotype against aminoglycoside-induced renal damage; further research designed to investigate the complexity of the renal handling of these drugs in these subjects would contribute to unravel the molecular mechanisms of aminoglycoside nephrotoxicity.

Nine patients with the unusual combination of renal failure, nephrotic-range proteinuria, and biopsy-proved interstitial nephritis are described. Six of these patients had received nonsteroidal anti-inflammatory agents (three fenoprofen, one ibuprofen, one zomepirac, and one tolmetin). The remaining three patients had no history of exposure to drugs known to cause interstitial nephritis. Immunologic characterization of the infiltrating cells with monoclonal antibodies showed that the majority of cells in most cases were cytotoxic T cells, although some B cells were present in all cases. Giant collecting duct cells were seen in half the patients with drug exposure but in none of the others. Otherwise, there were no conspicuous morphologic differences between patients with and without drug exposure. Many of the patients had associated glomerular abnormalities. Only the zomepirac and tolmetin recipients showed pure interstitial disease. The three fenoprofen recipients and the zomepirac and tolmetin recipients regained normal renal function after the drug was discontinued. The combination of renal failure, nephrotic range proteinuria, and interstitial nephritis is one form of nephrotoxicity observed in patients treated with nonsteroidal anti-inflammatory agents. However, this lesion, which may be mediated by cytotoxic T cells, may also be seen rarely in patients with no apparent drug exposure.