Dose Of Nabumetone Research Articles

Comparison of the effects of nabumetone with indomethacin on rat gastric mucosal 6-keto-PGF1α production and on bile salt-induced changes in gastric mucosal function

The effect of nabumetone on rat gastric mucosal cyclooxygenase activity ex-vivo and in-vitro has been compared with that of indomethacin. Nabumetone was less potent and less active in inhibiting the production of gastric mucosal 6-keto-PGF1 alpha compared with indomethacin either ex-vivo or in-vitro. Anti-inflammatory doses of nabumetone failed to enhance bile salt-induced gastric erosion or mucosal permeability to dextran whereas indomethacin significantly enhanced gastric erosion and increased dextran permeability. These results suggest that nabumetone fails to promote gastric damage or increase permeability because of minimal effects on gastric mucosal cyclooxygenase.

The efficacy, tolerability, and safety of 1200 mg/d of oxaprozin and 1500 mg/d of nabumetone in the treatment of patients with osteoarthritis of the knee

This 6-week, multicenter, double-masked, placebo-controlled study compared the efficacy, tolerability, and safety of the recommended starting dose of oxaprozin (1200 mg/d) and a 1500-mg/d dose of nabumetone in the treatment of patients with moderate-to-severe osteoarthritis (OA) of the knee. A total of 347 patients with a mean age of 61.1 years were randomized to receive oxaprozin (116 patients), nobumetone (115 patients), or placebo (116 patients). Adults of either sex who were older than 18 years of age were eligible for entry into the study, if they had had OA of the knee for at least 6 months. Efficacy variables included knee pain on weight bearing, knee pain on motion, patients' and physicians' global assessments of OA, pain intensity as measured on a visual analog scale, and time to walk 50 feet as quickly as possible. Efficacy variables were assessed at baseline and at weeks 1, 2, 4, and 6. Between-group differences in efficacy variables were evident by week 1. Mean improvements were significantly greter with oxaprozin than with placebo for all efficacy variables at all time periods, except knee pain on motion at weeks 2 and 4 and time to walk 50 feet at weeks 1, 2, and 4. Mean improvements were significantly greater with nabumetone than with placebo for all efficacy variables at all time periods, except the following: knee pain on weight bearing at weeks 2, 4, and 6; knee pain on motion at weeks 2 and 4; patients' global assessment at week 4; and pain intensity as measured on a visual analog scale at weeks 2 and 4. There were, however, no significant differences between oxaprozin and nabumetone in any of these efficacy variables. Adverse events were reported by 83 (71.6%) patients who took exaprozin, by 80 (69.6%) patients who took nabumetone, and by 57 (49.1%) patients who took placebo. Adverse events were reported for significantly more patients taking oxaprozin or nabumetone than placebo. However, adverse events tended to be mild or moderate and rarely resulted in patients withdrawing from the study. Combined with the results of an earlier study, the results of this showed that a 1500-mg/d dose of nabumetone, which is higher than the recommended starting dose of 1000 mg/d, is required for efficacy equivalent to that of the recommended starting dose of oxaprozin, 1200 mg/d, in relieving the symptoms of OA. Thus nabumetone may require dosage titration from the recommended starting dose. Oxaprozin and nabumetone were found to have similar tolerability profiles, as shown by adverse-event monitoring and withdrawal rates, as well as clinically similar safety profiles, as demonstrated by physical examinations, hematologic and biochemical laboratory testing, hemoccult testing, and adverse-event monitoring and symptom assessment.

Bioequivalence study of nabumetone tablets in man

A nabumetone tablet in development (NabutonR) was tested for its bioequivalence to the reference tablet (UnitonR). Seventeen healthy Korean male subjects participated in this study. Each subject received a 1-g dose of nabumetone (2 tablets each) in an unbalanced, randomized, two-way crossover investigation. Serum concentrations of 6-methoxy-2-naphthylacetic acid (6-MNA), a major metabolite of nabumetone, were measured over 120 hr interval by a high-performance liquid chromatography. The maximum serum concentration (Cmax) and time to reach the maximum concentration (Tmax) were read directly, but area under the serum concentration time curve from time 0 to 120 hr (AUC) and mean residence time (MRT) of 6-MNA were calculated from the serum 6-MNA concentration-time curves. The serum curves showed multiple peaks of 6-MNA in most subjects, and the Cmax and Tmax were read from the highest serum peaks. Calculated bioavailability parameters for test and reference tablets were 1498.6∶1377.9 μg·hr/ml for AUC; 25.2∶23.1 μg/ml for Cmax; 11.8∶16.4 hr for Tmax and 42.6∶43.8 hr for MRT, respectively. The pairedt-test revealed no significant differences in all the parameters between the two tablets. Analysis of variance (ANOVA) revealed no significant differences between groups and formulations in all the parameters (Cmax, Tmax, AUC and MRT) indicating the crossover design of the experiment was properly performed. But significant differences (p<0.05) between subject/groups and periods were found for all the parameters indicating substantial intersubject and interperiodic variations for these parameters.

Population pharmacokinetics of the active metabolite of nabumetone in renal dysfunction.

We determined the pharmacokinetics of 6-methoxy-2-naphythylacetic acid (6-MNA), the active metabolite of nabumetone, in normal subjects and in subjects with impaired renal function, including subjects requiring hemodialysis. Subjects received a 1000 mg oral dose of nabumetone either as a single dose or daily for 15 days. We used a noncompartmental pharmacokinetic analysis and compared those results to a population pharmacokinetic analysis performed with nonlinear mixed-effects modeling (NONMEM). The results of the two different analyses were similar. The elimination half-life increased with decreased renal function and ranged from 22 to 44 hours. The area under the curve decreased significantly at steady state, regardless of renal function. The apparent clearance determined by NONMEM analysis increased from 0.68 L/hr after a single dose to 1.13 L/hr at steady state. The apparent volume of distribution was directly proportional to the nonalbumin protein concentration and ranged from 23 to 60 L. We conclude that the pharmacokinetics of 6-MNA in this population are complicated by possible protein binding changes. However, the increased half-life in patients with renal failure is offset by changes in the apparent volume of distribution that prevent the accumulation of 6-MNA in the serum of patients with impaired renal function. Therefore dosage adjustments may not be necessary in patients with decreased renal function.

Comparative Effects of Nabumetone, Naproxen, Piroxicam, and Diclofenac on Rat Gastric lrritancy Following Acute Exposure to OTC Non-steroidal Anti-inflammatory Agents and Other Gastric Irritants

This study examined the relative effects of equally-effective anti-inflammatory doses of nabumetone, naproxen, piroxicam and diclofenac on gastric irritancy induced by over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and ibuprofen and a variety of necrotizing agents (0.6 N HCl, 0.2 N NaOH and 25% NaCl). Within one hour, aspirin 100 and 200 mg/kg and ibuprofen up to 15 mg/kg produced significant gastric mucosal injury. Aspirin 50 mg/kg produced only minimal damage that was enhanced by 5 x ID25 piroxicam and naproxen, but not by nabumetone or diclofenac. 5 x ID25 naproxen, piroxicam, and diclofenac significantly enhanced mucosal damage produced by ibuprofen 2.5 mg/kg. An equivalent anti-inflammatory dose of nabumetone failed to enhance the gastric irritancy produced by ibuprofen 2.5 mg/kg. Similarly, naproxen, piroxicam, and diclofenac enhanced the susceptibility of the gastric mucosa to the necrotizing actions of 0.6 N HCl, 0.2 N NaOH or 25% NaCl. Naproxen, piroxicam, or diclofenac are more likely than nabumetone to enhance gastric mucosal injury produced by OTC NSAIDs (aspirin and ibuprofen) or other gastric irritants.

Penetration of the Active Metabolite of Nabumetone into Synovial Fluid and Adherent Tissue of Patients Undergoing Knee Joint Surgery

The concentration of 6-methoxy-2-naphthylacetic acid (6-MNA) in plasma, synovial fluid, synovial tissue and fibrous capsule tissue was determined in an open study with 20 patients scheduled for knee joint surgery after oral treatment with nabumetone under steady-state conditions. 6-MNA is the principle metabolite of the prodrug nabumetone arising from an extensive first-pass metabolism in the liver. Patients suffering from rheumatoid arthritis (n = 12) or osteoarthritis stage III or IV (n = 8) received a daily dose of nabumetone 1 g in the evening starting 4 days prior to surgery. On day 1 an additional loading dose of nabumetone 1 g was given in the morning. At the time of surgery (day 5), blood, synovial tissue and fibrous capsule tissue were taken simultaneously. The samples were analysed by high performance liquid chromatography. After 4 days of treatment mean 6-MNA concentration in plasma was 40.76 mg/L, in synovial fluid 34.79 mg/L, in synovial tissue 19.33 mg/g and in fibrous capsule tissue 11.43 mg/g. Under steady-state conditions mean synovial fluid levels of 6-MNA were higher than after administration of a single dose and, in common with levels in synovial tissue, persist in a range sufficient for in vitro cyclo-oxygenase inhibition.

German Drug Monitoring Studies with Nabumetone

Although randomised controlled comparative trials concerning the efficacy of the drug tested can produce reliable results in a limited number of selected patient groups, drug monitoring studies involving 10,000 patients or more are the methods of choice to detect rare adverse events. The aim of this drug monitoring study was to evaluate the efficacy and safety of dispersible nabumetone tablets. 8865 patients (46.2% male, 53.5% female, mean age 55 years, range 14.95) were involved in the investigation carried out by 1172 general practitioners. The disease indications comprised osteoarthritis (69.8%), soft-tissue rheumatism (11.3%), rheumatoid arthritis (9.9%) and soft tissue injuries (7.7%). Most of the patients (67.3%) received a daily dose of nabumetone 1 g for up to 6 weeks. Efficacy was evaluated at baseline, and after 1 week, 3 weeks and 6 weeks of treatment. With regard to global efficacy, overall improvement (symptoms resolved or markedly improved) was assessed in 82% of the patients. Elimination or at least significant improvement of pain on movement occurred in 95%, pain on pressure in 90% and pain at rest in 89% of the patients with symptoms. In relation to swelling, morning stiffness and joint mobility, elimination or at least significant improvement occurred in 79%, 80% and 82% of patients, respectively. 1846 patients (20.8%) had frequent periods of NSAID-related symptoms before treatment with nabumetone. A total of 1174 adverse events occurred in 850 patients (9.6%), most comprising minor gastrointestinal complaints. Considering that at least 25,000 patients have been documented in 2 German drug monitoring studies, it is therefore unlikely that any unexpected side effects will occur in the future. Consequently, nabumetone can be classified as an effective and safe NSAID.