Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients.

BACKGROUND: S-adenosylmethionine (SAMe) has antiinflammatory and analgesic effects and has been reported to ameliorate the pain and dysfunction of osteoarthritis (OA). The metabolism of SAMe can be affected by geographic or ethnic factors. However, its efficacy and tolerability versus NSAIDs have not been reported in an Asian population. OBJECTIVE: This study compared the efficacy and tolerability of SAMe 1200 mg/d and nabumetone 1000 mg/d in Korean patients with knee OA. METHODS: This study was an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV clinical trial. Eligible patients were aged >18 years and had knee OA according to the clinical and radiologic criteria of the American College of Rheumatology, with a symptom duration of > or =3 months and with a baseline pain rating of >40 mm on a visual analog scale (VAS) or a pain rating on the VAS that was increased by >10 mm or 20% during the washout period compared with the screening visit. After a washout period of 2 weeks, patients with OA were randomly assigned to receive SAMe 1200 mg/d (400 mg TID) or nabumetone 1000 mg once a day in the evening for 8 weeks. The primary end point was the patient's assessment of pain intensity using a VAS at week 8, and the secondary end points were functional class, patient's global assessment of disease status, physician's global assessment of response to therapy, and the Western Ontario and McMaster Universities (WOMAC) index. Adverse events were assessed based on spontaneous reports by patients during interviews and by laboratory tests. RESULTS: One hundred thirty-four patients, all Asians, were randomly allocated to 1 of 2 treatment groups: 67 patients (56 women, 11 men; mean [SD] age, 63.9 [8.2] years) received SAMe 400 mg TID, and 67 patients (60 women, 7 men; mean age, 62.1 [8.4] years) received nabumetone 1000 mg once daily for 8 weeks. An analysis of changes in pain intensity between weeks 0 and 8 found that both SAMe and nabumetone effectively reduced pain intensity from baseline in each group (mean [SD] change: SAMe, -13.0 [20.8] mm, P < 0.001; nabumetone, -15.7 [20.9] mm, P < 0.001), and the degree of decrease in pain intensity was not significantly different between groups. Secondary end points showed significant improvements from baseline to 8 weeks in both groups. The patient's global assessment of disease status, physician's global assessment of response to therapy, and WOMAC index scores were not significantly different between the groups. Use of acetaminophen as rescue medication did not differ significantly between the groups during weeks 0 to 4 (SAMe, 88.5% [54/61]; nabumetone, 81.3% [52/64]) or weeks 4 to 8 (SAMe, 79.5% [35/44]; nabumetone, 68.5% [37/54]). No significant differences were observed between the treatments in the proportions of patients with all adverse events (SAMe, 35.8% [24/67]; nabumetone, 31.3% [21/67]), drugrelated clinical or laboratory-determined adverse events (SAMe, 22.4% [15/67]; nabumetone, 25.4% [17/67]), or discontinuations due to any adverse events (SAMe, 13.4% [9/67]; nabumetone, 10.4% [7/67]). CONCLUSION: This study found no significant differences in pain relief or tolerability between treatment with SAMe or nabumetone over 8 weeks in Korean patients with knee OA.

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.

Evaluation of current biological exposure index for occupational N, N-dimethylformamide exposure from synthetic leather workers.

The aim of this study was (1) to investigate the correlation between external exposure to N, N-dimethylformamide (DMF) and urinary excretion of DMF and N-methylformamide; (2) to assess whether the correspondence between the current occupational exposure limit setting and recommended urinary biological exposure index is substantial; and (3) to evaluate whether coexposure to toluene, methyl ethyl ketone, and ethyl acetate has an effect on urinary excretion of DMF and N-methylformamide (NMF). Urinary DMF and NMF were significantly correlated (P < 0.01) with one another and also significantly correlated with airborne DMF (P < 0.01) over the range of 1.55 to 152.8 mg/m. Urinary DMF can be considered a complementary marker for short-term exposure. Urinary concentration of NMF and DMF, corresponding to the 8-hour exposure to airborne DMF at 30 mg/m, was estimated to 38.4 mg/L or 39.4 mg/g creatinine for NMF and to 0.92 mg/L or 0.96 mg/g creatinine for DMF.

Risk factors of adverse drug reaction from non-steroidal anti-inflammatory drugs in Shanghai patients with arthropathy.

AIM: The study was to screen the possible risk factors of adverse drug reaction (ADR) induced by non-steroidal anti-inflammatory drugs (NSAIDs) in Shanghai patients with arthropathy. METHODS: The subjects were randomly selected from a database of outpatients with arthropathy from 9 main hospitals in Shanghai. A door to door retrospective epidemiological survey was used to collect demographic information about the patients, both individual and familial. This included data on their medical histories, lifestyle and dietary habits, history of smoking and alcohol consumption, history of drug therapy, quality of life (QOL) prior to NSAIDs intake, history of NSAIDs therapy and its ADR events, etc. Descriptive statistical methods and univariate analysis were also used to identify possible risk factors for ADRs induced by NSAIDs. RESULTS: Of the 1002 patients surveyed, the average length of NSAIDs intake was 2 years. ADR incidence from different NSAIDs was high, in a range from 46.7 %-66.2 %. In general, the candidate risk factors for ADRs were different for each NSAID. Each of the candidate risk factors were defined and studied in order to evaluate its role in the determination of ADRs from NSAIDs. "Family history of ADRs caused by NSAIDs" was found to be a significant risk factor for the four commonly used NSAIDs: meloxicam, diclofenac, nimesulide, and nabumetone. CONCLUSION: A retrospective epidemiological survey was useful in detecting the risk factors for ADRs caused by NSAIDs. The study found that different NSAIDs might have different risk factors and that there is no single risk factor universally applicable to all NSAIDs.

Effects of an external exposure to 200 ppm methyl ethyl ketone on nasal mucosa in healthy volunteers.

OBJECTIVES: To investigate the effects of an acute exposure to 200 ppm methyl ethyl ketone on the nasal mucosa of healthy volunteers. METHODS: Nineteen healthy non-smoking men were exposed to 200 ppm methyl ethyl ketone and to a sham exposure in an exposure chamber, using a cross-over design. Mucociliary transport time was determined with the saccharine test. Interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNFalpha) were measured in nasal secretions. Subjective symptoms were assessed by questionnaire. RESULTS: Mucociliary transport time was significantly higher (660 vs. 600 s (medians), P = 0.01) after solvent exposure. Concentrations of IL-1beta and IL-8 were insignificantly elevated after exposure (IL-1beta: 83.8 pg/ml vs. 48.1 pg/ml, medians, P = 0.11; IL-8: 14471 pg/ml vs. 11080 pg/ml, P = 0.12), whereas those of IL-6 and TNFalpha remained unchanged. Subjects did not feel any irritation of nasal mucosa. CONCLUSION: Concentrations of organic solvents not exceeding their MAK values can cause subclinical rhinitis. The secretion of proinflammatory cytokines and impairment of mucociliary transport can explain the development of clinical rhinitis in highly exposed subjects.

Time courses of sensory irritations due to 2-butanone and ethyl benzene exposure: influences of self-reported multiple chemical sensitivity (sMCS).

The individually different effects of exposure to comparable levels of chemicals might be partly explained by dissimilar response sensitivity towards chemicals. Multiple chemical sensitivity (MCS) might be the clinical endpoint of this altered sensitivity. Concerning a subclinical range of chemical sensitivity, 'challenge studies' with people reporting chemical sensitivity are needed to improve the knowledge about such differences. The chemical and general environmental sensitivity questionnaire (CGES) is a standardized screening tool for the selection of this group. In the present study 24 healthy male volunteers, half of them classified as sMCS-subjects, were experimentally exposed to 2-butanone and ethyl benzene at different levels (TLV-level vs. odor threshold). The strength of self-reported sensory irritations (nasal and ocular) and symptoms of bad smell were assessed, prior, during, and after the 4 hours of exposure. The time courses of sensory irritations were affected by sMCS. Across all exposure periods sMCS-subjects showed increasing symptom scores while control-subjects did not. Symptoms of bad smell were affected by three exposure-related factors (substance, level, duration) without any additional influence from the sMCS factor. Starting from these results it could be concluded that the time-depending influence of reported chemical sensitivity is most prominent for subjective data of sensory irritations.

Effect of nabumetone and aspirin on colonic mucosal bleeding time.

BACKGROUND: The management of patients taking aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) who require colonoscopy remains controversial because of concerns over bleeding after biopsy or polypectomy. AIM: To determine whether patients using the NSAID nabumetone, a non-acidic prodrug with mixed activity against cyclooxygenase-1 (COX-1) and COX-2, exhibited prolonged mucosal bleeding times and how this might compare with mucosal bleeding times in patients using aspirin. METHODS: We assessed triplicate mucosal bleeding times in patients undergoing screening flexible sigmoidoscopy. We compared 90 patients who had taken no aspirin or NSAIDs within the previous 2 weeks, to 60 patients who had received nabumetone 1 g b.d. by mouth for the previous 2 weeks, and 30 patients who had taken 325 mg aspirin daily for the previous 2 weeks. In each case, the investigator performing the study was blinded to the patient's medication. RESULTS: Mucosal bleeding times did not differ significantly among control or nabumetone-using patients. However, the patients receiving aspirin exhibited significant prolongation. Mucosal bleeding time correlated statistically significantly, but weakly, with skin bleeding time. CONCLUSIONS: Nabumetone does not appear to prolong mucosal bleeding time after mucosal pinch biopsy, and skin bleeding time does not reliably screen for prolonged mucosal bleeding time.

Liver damage among shoe repairers.

BACKGROUND: The risk of hepatotoxicity in the shoe industry has already been suggested, however, there has been no investigation among the craftsmen who repair shoes. METHODS: A group of 33 shoe repairers who work in supermarkets, and who use the same glues which contain mixtures of potentially hepatotoxic solvents were identified. A control group of 61 workers not exposed to hepatotoxic substances was also examined. All participants completed a questionnaire designed to identify potential risk factors and the main non-occupational confounding factors for hepatotoxicity. Laboratory tests, commonly used in clinical practice, were done to check whether they were useful markers of hepatotoxicity due to exposure to solvent mixtures, and to investigate which tests should be used in the screening campaigns. RESULTS: The exposed workers had a higher prevalence of elevated mean alanine aminotransferase (ALT), aspartate aminotransferase (AST), conjugated bilirubin (P=0.0001), and alkaline phosphatase (AP) (P=0.004) than controls did. The number of workers who had values outside the upper limit of normal for our laboratory was significantly higher (ALT P=0.034, AST P=0. 037, conjugated bilirubin P=0.014). Exposed workers all had a ratio of ALT to AST greater than 1, with a mean of 1.5; it was > 1.6 in more than half the exposed workers. CONCLUSIONS: The findings suggest that there is the possibility of liver involvement among even asymptomatic shoe repairers, and that periodic liver screening may be useful; furthermore, use of these tests (especially the ratio of ALT to AST) for craftsmen who repair shoes, and are exposed to solvent mixtures, is advisable even when environmental monitoring indicates levels below the threshold limit values (TLVs).

Effects of occupational chronic co-exposure to n-hexane, toluen, and methyl ethyl ketone on NK cell activity and some immunoregulatory cytokine levels in shoe workers.

1. To evaluate the effects of occupational long-term co-exposure to n-hexane, toluen, and methyl ethyl ketone (MEK) on NK cell activity and serum IL-2, gamma-IFN levels, we studied a group of workers employed in a shoe factory where the jobs include use of glues and adhesives containing mainly n-hexane, and at low concentrations, toluen and MEK. 2. No differences were found in these parameters even in those workers with 3.3-fold higher mean levels of urine, 2,5-Hxdn and approximately twofold higher mean levels of urine hippuric acid as compared to controls. 3. We conclude that chronic co-exposure to n-hexane, toluen, and MEK at these levels is not associated with an impairment on either NK cell activity or serum IL-2 and gamma-IFN levels.

Nabumetone induces less gastrointestinal mucosal changes than diclofenac retard.

The aim of the study was to compare the efficacy and the effects on the mucosa of the gastrointestinal tract (GIT) of nabumetone and diclofenac retard in patients with osteoarthritis (OA). An open, multicentre, randomised, comparative, endoscopy-blind parallel group study included 201 patients with nabumetone and 193 patients with diclofenac retard suffering from moderate to severe OA of the knee or hip joint. Twelve clinical efficacy variables were assessed and a portion of the population underwent gastroduodenoscopy. All patients exhibited significant improvement in pain severity and pain relief (p < 0.001 and p < 0.0001, respectively) but there were no differences between the groups for all the efficacy variables. Eleven per cent of patients on nabumetone and 19% on diclofenac experienced GIT side-effects. Sixty-nine patients with nabumetone and 61 with diclofenac underwent gastroduodenoscopy. The differences in the mucosal grade for the oesophagus, stomach and duodenum at baseline were not significant. In the oesophagus there were significantly less changes after treatment with nabumetone (p = 0.007) than with diclofenac; there were similar findings in the stomach (p < 0.001) but the difference in the duodenum was not significant. This study indicates that nabumetone and diclofenac retard have similar efficacy in the treatment of OA, but nabumetone has significantly fewer GIT side-effects.

Pseudoporphyria induced by nabumetone.

Nabumetone is a nonsteroidal anti-inflammatory drug, which has only rarely been associated with photosensitivity. We report a case of bullous lesions arising over photoexposed areas in a patient treated with nabumetone.

Gastrointestinal safety profile of nabumetone: a meta-analysis.

Individual comparative studies suggest that nabumetone has a gastrointestinal (GI) safety profile superior to comparator NSAIDs but lack power to show a statistical difference. The aim of this study was to evaluate systematically the difference in GI adverse events--especially the rate of perforations, ulcers, and bleeds (PUBs)-- between studies, meta-analyses of comparative trials of nabumetone and conventional NSAIDs, and postmarketing, open-label studies of nabumetone meeting predefined inclusion and exclusion criteria. A fully recursive literature search identified 13 studies consisting of 29 treatment arms and 49,501 patients that met the predefined criteria. Tests for heterogeneity found no significant difference between studies of each subgroup. Overall, the dyspeptic symptoms flatulence, constipation, and diarrhea were the most commonly reported adverse events accounting for 98.6% of the total GI adverse events. Significantly more patients treated with a comparator NSAID experienced GI adverse events than did those taking nabumetone (P = 0.007). After adjustment for patient-exposure years, PUBs were 10 to 36 times more likely to develop in patients treated with a comparator NSAID than with nabumetone. This was consistently seen in patients in nonendoscopic (n = 7,468) and endoscopic studies (n = 244). In the analysis of postmarketing or open-label studies of nabumetone, only one PUB was reported per 500 patient-exposure years over 17,502 treatment years (n = 39,389). GI adverse event-related dropouts and hospitalizations were increased by 1.3- and 3.7-fold if patients were treated with a comparator NSAID than with nabumetone. Significantly fewer treatment-related GI adverse events, especially PUBs, are seen in patients treated with nabumetone than with a comparator NSAID. Nabumetone is very safe for the GI tract.

Clinical efficacy and tolerance of nabumetone in articular and non-articular rheumatic disorders: personal experience during 12 weeks of treatment.

BACKGROUND: We evaluated the clinical efficacy and the tolerance of Nabumetone (N), in comparison with a pool of non-steroidal anti-inflammatory drugs (NSAIDs), in a cohort of patients affected by rheumatoid arthritis, osteoarthritis, non-articular rheumatisms and primary fibromyalgic syndrome. METHODS: One hundred and seventy patients were observed in an open-non randomized study. The patients have been recruited alternatively and subdivided into two groups: 84 patients that received N and 86 patients that received one of the other NSAIDs. All the patients affected by rheumatoid arthritis received a disease-modifying anti-rheumatic drug (OH-chloroquine, d-penicillamine, auranofin, cyclosporine-A); while benzodiazepines are administered in the patients suffering from primary fibromyalgic syndrome. A follow-up not inferior to 12 consecutive weeks was realized and the following clinical parameters were studied: spontaneous pain, provoked pain, pain on active movement, pain on passive movement, pain at rising, pain at bed time, morning stiffness, limited joint mobility, number of tender points, number of affected joints and number of swollen joints. All the patients were monitored for hematological, biochemical, urinary and clotting tests. RESULTS: The results revealed an excellent tolerability of nabumetone with a clinical efficacy not inferior to the NSAIDs' pool. Moreover, the number of drop-outs in the N-group were significantly inferior in comparison to the NSAIDs'-pool group. CONCLUSIONS: We conclude that N can be considered as effective as other NSAIDs. Moreover it seems to be better tolerated that the other NSAIDs utilized in our study.

Effect of nabumetone on hemostasis during arthroscopic knee surgery.

The known effects of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) on hemostatic parameters have led to concern over their use in the perioperative period. Nabumetone, unlike other NSAIDs, has little effect on collagen-induced platelet aggregation. To evaluate the effect of nabumetone 2000 mg daily on other hemostatic parameters (e.g., bleeding time, prothrombin time, and partial thromboplastin time) in the clinical setting, this double-masked study was conducted in patients with osteoarthritis undergoing arthroscopic knee surgery. After a 1-week placebo washout period, 58 patients were randomized to receive nabumetone and 53 were randomized to receive placebo. They were assessed before surgery (after 1 to 2 weeks of treatment) and again after surgery (after an additional 3 weeks of treatment). The study was designed to have 90% power to show equivalence in bleeding time to within 1.5 minutes, a difference assumed to be of no clinical importance. No meaningful differences were observed between the groups in any of the measured hemostatic parameters. Before surgery, the bleeding time increased by only 0.3 minutes with nabumetone and decreased by 0.2 minutes with placebo. The mean (+/- SD) difference between the groups in change from baseline was 0.5 +/- 0.3 minutes. After surgery, the changes were 0.1 minutes and 0.0 minutes, respectively, and the difference between groups was 0.2 +/- 0.3 minutes. These differences were neither statistically nor clinically significant, and maximum individual increases were similar in each group. Furthermore, there were no reports of abnormal bleeding in the operative knees. The results of this study show that nabumetone had little or no effect on hemostasis and suggest that this drug can be used safely in the perioperative period.

Nabumetone-associated interstitial nephritis.

An 84-year-old woman was admitted to the hospital for progressive edema and decreased urine output. She had been taking nabumetone for 6 months, but had discontinued the agent 2 weeks before admission due to progressive edema. On admission she had 2-3+ pitting edema. Her serum electrolytes were sodium 122 mEq/L, potassium 5.9 mEq/L, chloride 93 mEq/L, and carbon dioxide 19 mEq/L. A urinalysis was significant for protein 3061 mg/dl, ketones 15 mg/dl, blood 2+, leukocytes 26-50/high-power field, and a protein:creatinine ratio 24.9. The serum creatinine and blood urea nitrogen concentrations were 2.7 mg/dl and 70 mg/dl, respectively. Throughout hospitalization the patient underwent aggressive diuresis. She developed congestive heart failure, and hemodialysis was initiated. A renal biopsy specimen on hospital day 9 showed tubular damage with minimal glomerular changes consistent with a diagnosis of nonsteroidal agent-induced nephropathy. On day 13, a 24-hour urine collection had a protein excretion of 3151 mg. Although the patient recovered from her renal failure (creatinine clearance 43 ml/min), the nephrotic syndrome persisted (13 g protein/day). The patient developed infectious complications and died on hospital day 32.