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Biomedical subjects

A Whelton

Publications and source records attributed to A Whelton.

At least 19 recordsLinked to original sources
PubMed2006

Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen.

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N = 2183; OA: N = 5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N = 3987); ibuprofen, 800 mg three times a day. (N = 1985); or diclofenac, 75 mg b.i.d. (N = 1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P < 0.05) and ibuprofen (7.3%; P < 0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.

Acid-Base Equilibrium↗
PubMed2001

A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database.

BACKGROUND: Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2-specific inhibitors inhibit only the COX-2 isoform. OBJECTIVE: This study sought to compare renal safety signals between the COX-2-specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000. METHODS: Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality. RESULTS: As with traditional NSAIDs, both COX-2-specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen. CONCLUSIONS: Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Acute Kidney Injury↗
PubMed2000

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. MAIN OUTCOME MEASURES: Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. RESULTS: For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255

Aged↗
PubMed2000

Effects of celecoxib and naproxen on renal function in the elderly.

OBJECTIVE: To compare the effects of celecoxib, a cyclooxygenase 2-specific inhibitor, with the nonspecific cyclooxygenase 1 and 2 inhibitor naproxen on renal function in 29 healthy elderly subjects in a single-blind, randomized, crossover study. METHODS: Subjects received either celecoxib, 200 mg twice daily, for 5 days followed by celecoxib, 400 mg twice daily, for the next 5 days, or they received naproxen, 500 mg twice daily, for 10 days. After a 7-day washout, subjects were crossed over to receive the other regimen. RESULTS: After the first dose, the trend was for a greater decrease in glomerular filtration rate with naproxen (-5.31 mL/min per 1.73 m2) compared with celecoxib (-0.86 mL/min per 1.73 m2). The treatment difference became statistically significant on day 6 (-7.53 vs -1.11 mL/min per 1.73 m2 for naproxen and celecoxib, respectively; P=.004). Urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion was significantly reduced from baseline across the treatment interval with both celecoxib and naproxen (P< or =.04). There were no significant differences in prostaglandin excretion between these 2 agents (P> or =.07). Small, transient decreases (P<.05) in urinary sodium excretion were observed after the initiation of both celecoxib and naproxen treatment. Sodium excretion values returned to baseline by the end of the study. CONCLUSIONS: The results indicate that cyclooxygenase 2-specific inhibition in healthy elderly subjects may spare renal hemodynamic function, although the effects on sodium excretion, as well as urinary prostaglandin E2 and 6-keto-prostaglandin F1alpha excretion, appear to be similar to those of nonspecific cyclooxygenase inhibitors such as naproxen.

Aged↗
PubMed2000

Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatment of rheumatoid arthritis.

OBJECTIVE: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. METHODS: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. RESULTS: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. CONCLUSIONS: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage.

Antirheumatic Agents↗
PubMed2000

Renal and related cardiovascular effects of conventional and COX-2-specific NSAIDs and non-NSAID analgesics.

On a daily basis it appears that as many as one in five adults in the United States may consume an analgesic compound either on a prescription basis or by over-the-counter (OTC) purchase. This high profile of intermittent or repetitive analgesic use appears to be relatively similar throughout the developed world. Although analgesics generally have a good renal safety profile, the nonsteroidal anti-inflammatory drug (NSAID) analgesics may produce mild renal side effects, such as the generation of peripheral edema in up to 5% of the general population. Other more serious renal and related cardiovascular side effects tend to be more apparent in lesser numbers of clinically "at risk" NSAID analgesic users. In contrast, non-NSAID analgesics, such as paracetamol or tramadol, have essentially no renal or related cardiovascular side effects when used at recommended dosing schedules. This review characterizes the renal syndromes associated with the use of NSAID analgesics, identifies the risks inherent in the use of these compounds in treated patients with hypertension and congestive heart failure, summarizes the early comparable data available for the new COX-2-specific inhibitors, and profiles the scant acute and long-term clinical concerns attendant with the use of non-NSAID nonnarcotic analgesics. It is important that healthcare providers and practitioners are aware of the relative renal risks of different analgesics and that they use this knowledge to counsel the analgesic-consuming population appropriately.

Acetaminophen↗
PubMed2000

Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor.

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.

Age Factors↗
PubMed1999

Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.

Although the prevalence of nephrotoxicity in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) is relatively low, the extensive use profile of these agents implies that many persons are at risk. At basal states of normal renal function, the role of renal prostaglandin production for maintenance of stable renal hemodynamic function is relatively limited. Nonetheless, in the clinical setting of reduced renal perfusion as seen in various forms of cardio-renal disease, dehydration, and the aging kidney, the adequacy of renal prostaglandin production mediated predominantly by cyclooxygenase-1 (COX-1) and, potentially, by COX-2 enzyme activity becomes of major significance in the activation of compensatory renal hemodynamics. Inhibition of renal prostaglandin production by the use of NSAIDs in these circumstances can potentially lead to the emergence of several distinct syndromes of disturbed renal function. These include fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome/ interstitial nephritis, and renal papillary necrosis. In addition, by blunting the homeostatic renal effects of prostaglandins, NSAIDs can adversely influence blood pressure control, particularly during the use of angiotensin-converting enzyme (ACE) inhibitors, diuretics, and beta blockers. This is a matter of considerable public health concern, in that some 12 million US citizens are concurrently treated with NSAIDs and antihypertensive drugs. Finally, the risk of congestive heart failure is significantly increased when NSAIDs are given to patients receiving diuretic therapy who have cardiovascular risk factors. Physiologic factors, clinical presentations, diagnostic modalities, and clinical management strategies appropriate to these NSAID-induced renal syndromes are described.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Assessing the clinical need for short-term conversion from oral to parenteral angiotensin converting enzyme inhibitor therapy in hypertensive patients. A quinapril to quinaprilat placebo-controlled model.

UNLABELLED: RATIONALE AND STUDY DESIGN: This study assesses safety and efficacy when hypertensive patients convert from an oral angiotensin converting enzyme inhibitor, quinapril, to its intravenous counterpart, quinaprilat, and evaluates the need for short-term conversion from oral to parenteral therapy. Blood pressure was measured by clinical measurements using a sphygmomanometer and by 24-h ambulatory blood pressure monitoring. During a placebo-baseline phase, patients blood pressure had to increase within 3 days in the absence of an angiotensin converting enzyme inhibitor. Responding patients were stabilized on oral quinapril and then randomized to 3 days of double-blind treatment with one 5 ml or 10 ml injection twice daily of quinaprilat or placebo. RESULTS: Overall response to quinaprilat in ambulatory blood pressure monitoring and clinic blood pressure measurements was not statistically or clinically different from the response to oral quinapril therapy during baseline. Withdrawal from quinapril resulted in clinically significant increases in all blood pressure measurements compared with baseline therapy; the differences between placebo and quinaprilat therapy were statistically and clinically significant. Two patients treated with quinaprilat withdrew due to hypotension; one patient required a dosage reduction. Parenteral quinaprilat safely maintained blood pressure control whereas placebo control did not during the 72-h interruption of quinapril.

Administration, Oral↗
PubMed1997

Acute renal papillary necrosis induced by ibuprofen.

Several specific renal syndromes may be induced by the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) upon renal function. We report an NSAID-induced form of acute renal failure that represents a dual mechanism of impact on renal function involving direct parenchymal damage at a renal papillary level and mechanical outflow ureteric obstruction consequent to acute papillary necrosis. This form of NSAID-related acute renal failure has been reported very infrequently. We suspect the syndrome is not often recognized clinically. Clinicians and health care workers need to remind constantly the general public concerning the standard steps to be taken to ensure the proper and safe use of over-the-counter drugs. This is especially important considering the recent FDA approval of the over-the-counter sale of naproxen sodium, ketoprofen, and ibuprofen.

Acute Kidney Injury↗
PubMed1995

Tricenter assessment of the efficacy of the ACE inhibitor, moexipril, by ambulatory blood pressure monitoring.

To assess the efficacy and time-dependent effects of once-daily moexipril, a nonsulfhydryl ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, moexiprilat, we conducted a multicenter, double-blind, placebo-controlled trial in 51 hypertensive patients using both clinic and ambulatory blood pressure (BP) recordings. Patients were included in the trial based on a minimum of 40% of the daytime diastolic BPs of 90 mm Hg or more during a placebo baseline phase; and the primary endpoint was change in 24-hour ambulatory diastolic BP. Patients were randomized to receive placebo, 7.5 mg of moexipril, or 15 mg of moexipril once daily. Clinic and ambulatory BPs were taken on the first day and after eight weeks of double-blind therapy. After the 7.5-mg dose, there were no significant changes in the acute or prolonged clinic BPs compared with placebo. Compared with adjusted mean changes for placebo, the 15-mg moexipril dose lowered clinic systolic BP, but not diastolic BP. In contrast, acute (1 day) reductions in 24-hour diastolic BPs were -2/-3 mm Hg, -6/-4 mm Hg, and -14/-9 mm Hg on placebo, 7.5 mg of moexipril, and 15 mg of moexipril, respectively (P < .01 for the 15-mg dose). Similarly, after long-term dosing for 8 weeks, reductions in 24-hour diastolic BPs were 1/-2 mm Hg, -6/-4 mm Hg, and -12/-9 mm Hg for the respective treatment groups (P < .01 for the 15-mg dose).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Renal effects of over-the-counter analgesics.

Recent case reports have shown that over-the-counter (OTC) analgesics, which are generally considered to be a safe treatment for minor aches and pains and fever, may cause adverse renal effects. Many renal syndromes induced by nonsteroidal antiinflammatory drugs (NSAIDs) can be attributed to prostaglandin inhibition. Fluid and electrolyte disturbances, acute renal failure, and acute interstitial nephritis also occur predominantly with NSAIDs. Acetaminophen lacks significant peripheral prostaglandin inhibition and may be a preferred first-line agent, particularly in patients susceptible to the induction of renal impairment. Apart from obvious clinical overdosage situations, limited reports of adverse renal effects exist with acetaminophen. Some studies have reported an association between analgesic nephropathy, one of the most severe analgesic-related adverse renal effects, and long-term abuse of phenacetin, acetaminophen, aspirin, ibuprofen, analgesic combinations, or other NSAIDs, although for some of these agents, this relationship is controversial. The overall risk for serious renal effects with OTC analgesics appears to be low, but given the accessibility and vast number of persons taking these agents, the absolute number of patients affected may be substantial. Therefore, it is important that healthcare providers recognize the risk factors for adverse analgesic-related renal effects.

Acetaminophen↗
PubMed1992

Ambulatory blood pressure monitoring: a new window to decision-making in hypertension.

Ambulatory blood pressure monitoring is more physiologically valid and more reliable than office or clinic blood pressure measurement, since it provides a realtime quantitative record of the 24-h diurnal blood pressure cycle rather than a random snapshot. Its chief clinical value is the provision of accurate baselines and in making possible the individualization of patient care. It can correctly characterize episodic elevations of blood pressure and detect true as opposed to borderline hypertension. Ambulatory blood pressure monitoring may be a better predictor of target-organ damage than office blood pressure measurements.

Ambulatory Care↗