Biomedical subjects

K M Verburg

Publications and source records attributed to K M Verburg.

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↗

PubMed2004

Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib.

AIM: In a predefined analysis, data were pooled from eight blinded, randomized, controlled trials, and separately from three long-term, open-label trials to determine the rate of upper gastrointestinal ulcer complications with the cyclo-oxygenase-2 selective inhibitor, valdecoxib, vs. non-selective non-steroidal anti-inflammatory drugs. METHODS: In randomized, controlled trials, 7434 osteoarthritis and rheumatoid arthritis patients received placebo (n = 973), valdecoxib 5-80 mg daily (n = 4362), or a non-selective non-steroidal anti-inflammatory drug (naproxen, ibuprofen or diclofenac; n = 2099) for 12-26 weeks. In long-term, open-label trials, 2871 patients received valdecoxib 10-80 mg daily for up to 1 year. All potential events were reviewed by a blinded, independent review committee based on a priori definitions of ulcer complications (perforations, obstructions, bleeds). RESULTS: In randomized, controlled trials, 19 of 955 potential events were adjudicated to be ulcer complications. Valdecoxib was associated with a significantly lower ulcer complication rate than non-selective non-steroidal anti-inflammatory drugs (0.68% vs. 1.96%, all patients; 0.29% vs. 2.08%, non-aspirin users; P < 0.05). In long-term, open-label trials, seven of 310 potential events were adjudicated to be ulcer complications; the annualized incidence for valdecoxib was 0.39% (seven of 1791 patient-years) for all patients and 0.2% (three of 1472 patient-years) for non-aspirin users. CONCLUSIONS: Valdecoxib, including above recommended doses, is associated with a significantly lower rate of upper gastrointestinal ulcer complications than therapeutic doses of non-selective non-steroidal anti-inflammatory drugs.

Adult↗

PubMed2003

A comparison of the upper gastrointestinal mucosal effects of valdecoxib, naproxen and placebo in healthy elderly subjects.

BACKGROUND: In long-term outcomes studies, cyclooxygenase COX-2 specific inhibitors spare COX-1 at supratherapeutic doses and therefore demonstrate improved gastrointestinal safety over nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs). However, in clinical practice, anti-inflammatory drugs are often used for short-term treatment of pain. AIM: To compare the short-term upper gastrointestinal mucosal effects of naproxen with the new COX-2 specific inhibitor, valdecoxib, or placebo, in elderly subjects. METHODS: In this multicentre, double-blind, randomized, study, elderly subjects (65-76 years old), with a normal baseline esophagogastroduodenoscopy (EGD), received oral valdecoxib (a supratherapeutic 40 mg b.d. dosage, n = 62), naproxen (500 mg b.d., n = 62), or placebo (n = 62) for 6.5 days. Upper gastrointestinal mucosal injury was evaluated post-treatment by EGD (day 7). RESULTS: Subjects receiving naproxen (11/60, 18%) had significantly more gastroduodenal ulcers post-treatment than those receiving placebo (2/61, 3%; P < 0.01) or valdecoxib (0/60, 0%; P < 0.001). A similar significant finding was observed for gastric ulcer rates. All treatments had similar adverse event rates and clinical laboratory findings. CONCLUSIONS: Valdecoxib, even at supratherapeutic doses, was associated with an ulcer rate significantly lower than naproxen but similar to placebo in healthy elderly subjects, despite the short duration of therapy (6.5 days). Naproxen and valdecoxib were as well tolerated as placebo.

Administration, Oral↗

PubMed2003

Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial.

OBJECTIVE: To compare the efficacy and upper gastrointestinal (GI) safety of valdecoxib 20 and 40 mg daily with those of diclofenac 75 mg slow release (SR) twice daily in treating rheumatoid arthritis (RA). METHODS: Seven hundred and twenty-two patients with adult-onset RA were enrolled into this 26-week, randomized, multicentre, double-blind, parallel-group study (246 in the valdecoxib 20 mg daily arm, 237 in the valdecoxib 40 mg daily arm and 239 in the diclofenac 75 mg SR daily arm). Acetylsalicylic acid use (< or =325 mg per day) was similar across all groups: 5.4% in the diclofenac group, 5.7% in the valdecoxib 20 mg group and 5.9% in the valdecoxib 40 mg group. Efficacy was measured by the Patient's Assessment of Arthritis Pain [visual analogue scale (VAS)] and the modified Health Assessment Questionnaire (mHAQ) at baseline and at weeks 2, 6, 8, 12, 18 and 26 of treatment, or at early termination. Upper GI safety was evaluated by endoscopy at the end of treatment, which took place no more than 2 days after the last dose of study medication or at early termination. RESULTS: Valdecoxib 20 and 40 mg daily were comparable to diclofenac 75 mg SR twice daily in treating the signs and symptoms of RA. No significant differences were observed between treatment groups with respect to mean changes from baseline in the Patient's Assessment of Arthritis Pain (VAS) or mHAQ. The incidence of gastroduodenal ulcers in patients receiving valdecoxib 20 mg daily (6%) and valdecoxib 40 mg daily (4%) was significantly lower (P < 0.001) than in patients receiving diclofenac 75 mg SR twice daily (16%). Valdecoxib 20 mg daily was also associated with significantly improved GI tolerability (P = 0.035) compared with diclofenac. CONCLUSIONS: Single daily doses of valdecoxib 20 and 40 mg provided efficacy comparable to that of diclofenac, with a superior upper GI safety profile in the long-term treatment of RA patients.

Adult↗

PubMed2001

Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults.

BACKGROUND: Current outpatient management of postoperative pain includes the use of oral opioid analgesics or nonsteroidal anti-inflammatory drugs; however, both types of medications are associated with side effects that can limit their usefulness in the outpatient setting. OBJECTIVE: Two studies with identical protocols assessed the single- and multiple-dose analgesic efficacy and tolerability of celecoxib, a specific cyclooxygenase-2 inhibitor, in the treatment of acute pain after orthopedic surgery. METHODS: These were multicenter, randomized, placebo- and active-controlled, double-blind, parallel-group trials conducted between January and June 1998. Both consisted of a single-dose assessment period (SDAP) and a multiple-dose assessment period (MDAP). In the SDAP, patients who had undergone orthopedic surgery received a single oral dose of celecoxib 200 mg, hydrocodone 10 mg/acetaminophen 1000 mg, or placebo within 24 hours after the end of anesthesia, with pain assessments conducted over the following 8-hour period. In the MDAP, extending from 8 hours after the first dose of study medication up to 5 days, patients who had received < or =1 dose of rescue medication during the SDAP continued on study medication (placebo recipients were rerandomized to active treatment), which could be taken up to 3 times a day as needed. RESULTS: A total of 418 patients were enrolled in the 2 trials. During the SDAP, 141 patients received celecoxib, 136 received hydrocodone/acetaminophen, and 141 received placebo. During the MDAP, 185 patients received celecoxib and 181 received hydrocodone/acetaminophen. When the combined data were analyzed, mean pain intensity difference (PID) scores generally favored the active treatments over placebo from 1 to 6 hours (with the exception of 1.5 hours) after dosing (P < or = 0.016) and favored celecoxib over the other treatments at 7 and 8 hours after dosing (P < 0.001). The active treatments demonstrated superior summed PID scores through 8 hours (P < 0.001), significantly shorter median times to onset of analgesia (P < 0.05), and significantly longer median times to first use of rescue medication (P < 0.05). During the MDAP, more hydrocodone/acetaminophen-treated patients (20%) than celecoxib-treated patients (12%) required rescue medication (P < 0.05), and the celecoxib group had significantly lower maximum pain intensity scores (P < 0.001, days 2-5), required fewer doses of study medication (P < or = 0.01, days 3-5), and had superior scores on a modified American Pain Society Patient Outcome Questionnaire (P < or = 0.013). In addition, a significantly lower proportion of celecoxib-treated patients experienced adverse events (43%) compared with hydrocodone/acetaminophen-treated patients (89%; P < 0.001). CONCLUSIONS: Over 8 hours, patients with moderate to severe pain after orthopedic surgery experienced comparable analgesia with single doses of celecoxib and hydrocodone/acetaminophen. Over a 5-day period, oral doses of celecoxib 200 mg taken 3 times a day demonstrated superior analgesia and tolerability compared with hydrocodone 10 mg/acetaminophen 1000 mg taken 3 times a day. Most patients required no more than 2 daily doses of celecoxib 200 mg for the control of their postorthopedic surgical pain.

Acetaminophen↗

PubMed2001

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. METHODS: In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. RESULTS: Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. CONCLUSIONS: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.

Adult↗

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

The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib.

Celecoxib is a cyclooxygenase- (COX)-1-sparing inhibitor of COX-2 that is indicated for the treatment of osteoarthritis and rheumatoid arthritis. Many agents used for treating these diseases, both symptom-modifying and disease-modifying, are associated with the potential for hepatotoxicity. This article presents an analysis of the hepatic effects of celecoxib in 14 controlled studies of patients with arthritis (2 to 24 weeks' duration), in a long-term, open-label safety study (as long as 2 years), in 11 studies of patients receiving treatment for pain after oral or orthopedic surgery (up to 5 days' duration), and in five pharmacology studies. The overall incidence of hepatic adverse events in arthritis patients receiving celecoxib was similar to that for placebo but significantly lower than in the combined group of patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). The most commonly reported hepatic adverse events were elevations in liver transaminase levels, most of which occurred in patients receiving diclofenac. Similarly, clinically significant elevations of transaminase levels occurred more frequently with NSAIDs than with celecoxib. A pharmacology study performed in patients with mild or moderate hepatic impairment showed that celecoxib did not produce any clinically relevant changes from baseline in creatinine clearance, alanine aminotransferase, or bilirubin values in these settings. In the four interaction studies performed with drugs metabolized in the liver, none of the adverse events was hepatic in nature, and no clinically relevant liver function test abnormalities occurred. In conclusion, this analysis suggests that celecoxib has a very low potential for hepatic toxicity, even after exposures of as long as 2 years at therapeutic doses.

Anti-Inflammatory Agents, Non-Steroidal↗

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↗

PubMed2000

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE: The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2-24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25-400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100-400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patient's treatment assignment or the study in which the patient participated. RESULTS: In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05 vs placebo) and 1.68% for NSAIDs (p = 0.002 vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%. CONCLUSIONS: The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Adolescent↗

PubMed1999

Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial.

CONTEXT: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition. OBJECTIVE: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis. DESIGN: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998. SETTING: Seventy-nine clinical sites in the United States and Canada. PATIENTS: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study. INTERVENTIONS: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231). MAIN OUTCOME MEASURES: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups. RESULTS: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen. CONCLUSION: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Adult↗

PubMed1999

Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with those of naproxen, a nonsteroidal anti-inflammatory drug (NSAID), and placebo in the treatment of osteoarthritis of the knee. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 1003 patients with symptomatic osteoarthritis of the knee were randomly assigned to receive celecoxib at doses of 50, 100, or 200 mg twice a day; naproxen, 500 mg twice a day; or placebo for 12 weeks. Patients were evaluated with standard measures of efficacy 2 to 7 days after discontinuing previous NSAID or analgesic therapy and after 2, 6, and 12 weeks of treatment with the study drug. RESULTS: Celecoxib treatment led to significant improvement in the signs and symptoms of osteoarthritis as determined by all efficacy measures. Significant pain relief occurred within 2 days of the initiation of treatment, and maximum anti-inflammatory and analgesic activity, evident within 2 weeks, was sustained throughout the 12-week study. All celecoxib doses were efficacious compared with placebo, although the 50-mg twice-daily dosage regimen was minimally effective. The higher doses of celecoxib (100 and 200 mg twice a day) were similarly efficacious, and the magnitude of improvement observed with these dosing regimens was comparable to that seen with naproxen at a dose of 500 mg twice a day. All doses of celecoxib and naproxen were well tolerated. CONCLUSION: COX-2 inhibition with celecoxib is an effective approach for the treatment of osteoarthritis, as seen by clinical improvement in signs and symptoms comparable to treatment with naproxen.

Adult↗

PubMed1994

Nonpeptide renin inhibitors with good intraduodenal bioavailability and efficacy in dog.

The aim of this study was the discovery of nonpeptide renin inhibitors with much improved oral absorption, bioavailability, and efficacy, for use as antihypertensive agents. Our prior efforts led to the identification of A-74273 [1,R = 3-(4-morpholino)propyl], with a bioavailability of 26 +/- 10% [10 mg/kg intraduodenally (id), dog]. In vivo metabolism studies of A-74273 showed that the morpholino moiety underwent metabolic degradation. Computer modeling of A-74273 bound to renin indicated that the C-terminus was involved in a hydrogen-bonding network. New C-terminal groups were examined in two series of nonpeptides for effects on renin binding potency, lipophilicity (log P), and aqueous solubility. Those groups which possessed multiple hydrogen-bonding ability (3,5-diaminotriazole, cyanoguanidines, morpholino) provided particularly potent renin binding. Intraduodenal bioavailabilities of selected compounds, evaluated in rats, ferrets, and dogs, were higher for inhibitors with moderate solubility as well as moderate lipophilicity, in general. Although the absolute values varied substantially among species, the relative ordering of the inhibitors in terms of absorption and bioavailability was reasonably consistent. Such well absorbed inhibitors (e.g. 41, 44, and 51) were demonstrated as highly efficacious hypotensive agents in the salt-depleted dog. We report here the discovery of a series of efficacious nonpeptide renin inhibitors based on the 3-azaglutaramide P2-P4 replacement, the best of which showed id bioavailabilities > 50% in dog.

Amides↗

PubMed1993

Effects of high doses of A-74273, a novel nonpeptidic and orally bioavailable renin inhibitor.

Previous studies with peptidic renin inhibitors have shown that high intravenous (i.v.) doses can induce unexpectedly large decreases in blood pressure (BP) that appear to be independent of plasma renin inhibition. A-74273 represents a new class of potent and orally bioavailable nonpeptidic renin inhibitors. We evaluated the BP effects of this renin inhibitor administered orally (p.o.) or i.v. at high doses to conscious salt-depleted dogs. Administration of A-74273 at 30 and 60 mg/kg p.o. (n = 6 per dose) produced similar maximum reductions in BP (-40 +/- 4 vs. -46 +/- 5 mm Hg) despite the occurrence of greater plasma drug concentrations at the higher dose. Duration of hypotension, however, was increased (p < 0.05) from 9 h at 30 mg/kg to 18 h at 60 mg/kg. The initial depressor response to 10 and 30 mg/kg i.v. doses of A-74273 (n = 6 per dose) was comparable, although duration and overall BP response was greater at 30 mg/kg i.v. No BP responses to A-74273 were noted in salt-replete dogs (n = 5). The hypotension produced by 30 mg/kg p.o. A-74273 was completely reversed by norepinephrine (NE 5 micrograms/kg/min; n = 5) or isotonic saline (4 ml/min/kg, n = 5) infusion. These studies demonstrate that high doses of A-74273 result in predictable BP responses that are renin-dependent and reversible. Therefore, large decreases in BP with high doses is not an attribute common to all renin inhibitors but appears to be a function of the structural characteristics specific to a particular compound.

Administration, Oral↗

PubMed1992

Discovery of a well-absorbed, efficacious renin inhibitor, A-74273.

The development of orally active renin inhibitors has been plagued by limited bioavailability in animals and humans. A-74273 is a novel, potent nonpeptide inhibitor of human renin (IC50 = 3.1 nM). This compound was absorbed into the portal and systemic circulations of anesthetized rats, ferrets, monkeys, and dogs after intraduodenal dosing. This favorable pattern also was observed after oral dosing in conscious animals, except in monkeys. Hepatic extraction of A-74273 was more efficient in rats and monkeys than in dogs or ferrets. A-74273 modestly inhibits dog renin, and when given orally as the base (0, 0.3, 1, 3, 10, and 30 mg/kg; n = 8 per dose) to conscious, salt-depleted dogs it induced dose-related reductions in mean arterial pressure and plasma renin activity. Peak falls in mean arterial pressure from normotensive baselines were -14 +/- 1, -26 +/- 3, and -44 +/- 3 mm Hg for the 3, 10, and 30 mg/kg groups, respectively (p < 0.05). Baseline plasma renin activity values (10.9 +/- 1.1-12.7 +/- 1.1 ng angiotensin I/ml/hr) were maximally inhibited, ranging from 43 +/- 8% at 0.3 mg/kg to 98 +/- 1% at 30 mg/kg. Bioavailability in this model was estimated to be 54 +/- 13% when plasma drug levels were determined by a renin inhibitory activity assay, but bioavailability was lower when compared with high-performance liquid chromatographic analysis of A-74273. This discrepancy was accounted for by the identification of structurally similar metabolites that are as active as the parent drug against human renin but much less potent against dog renin.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed1991

Radioenzymatic assay for histamine: development and validation.

Radioenzymatic assays are sensitive analytic tools that use an enzyme to quantify a substrate for that enzyme. Purified histamine N-methyltransferase has been used as the basis for an assay for histamine. The sensitivity of the procedure is less than 10 fmol. The specificity of the assay is increased when the transferase reaction is carried out at 0-3 degrees C. Data documenting the precision of the assay, the stability of histamine in human plasma, and the gastric secretory rate of histamine are presented along with a chronologic description of the development of the technique.

Adult↗

PubMed1990

Effect of intrarenal renin inhibition on renal hemodynamics and excretory function.

This study was designed to investigate in sodium-depleted monkeys the renal hemodynamic and excretory effects resulting from blockade of the renin-angiotensin system induced by intrarenal infusion of the primate-selective renin inhibitor A-65317. Intrarenal infusion of A-65317 (n = 6) at a dose of 0.01 micrograms.kg-1.min-1 elicited an increase (P less than 0.05) in renal blood flow (RBF) from 43.5 +/- 2.7 to 49.4 +/- 4.4 ml/min and glomerular filtration rate (GFR) from 6.3 +/- 0.3 to 6.9 +/- 0.4 ml/min, with no significant changes in mean arterial pressure (MAP) or plasma renin activity (PRA). Increases (P less than 0.05) in the urine flow rate (0.18 +/- 0.04 to 0.28 +/- 0.04 ml/min) and the fractional excretion of sodium (0.18 +/- 0.06 to 0.35 +/- 0.13%) were also observed. After a recovery period, the intrarenal infusion dose of A-65317 was increased to 0.1 microgram.kg-1.min-1 and RBF increased (P less than 0.05) from 42.9 +/- 3.9 to 53.0 +/- 3.7 ml/min in conjunction with a significant 85 +/- 4% inhibition of PRA and a 14 +/- 4 mmHg reduction in MAP. GFR and electrolyte excretion remained at control levels. Intrarenal infusion of vehicle (n = 6) had no significant effect on any of the variables studied. In a separate group of monkeys, intravenous (iv) infusion of A-65317 at 0.01 microgram.kg-1.min-1 (n = 5) did not result in significant changes from control.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗