In the otherwise excellent article by Lanas et al,1 as with most other articles examining the putative role of nonsteroidal anti-inflammatory drugs (NSAIDs) in gastrointestinal (GI) bleeding, I fear that insufficient attention is being paid to the differences among NSAIDs in half-life, and to the actual dosing regimens used in the patients studied.

GOALS:To evaluate the efficacy and gastrointestinal safety of nabumetone and diclofenac in the treatment of elderly patients with osteoarthritis, participating in a 3-month efficacy trial.BACKGROUND:Elderly patients have an elevated risk for developing gastrointestinal complications with chronic use of nonsteroidal anti-inflammatory drugs.STUDY:This was a randomized, double-blind, parallel-group, multicenter study with a 3-to 14-day placebo washout period and a 12-week active treatment phase. Patients 65 years or older with moderate-to-severe osteoarthritis of the knee or hip were randomized to receive 1,000 to 2,000 mg/d of nabumetone or 100 to 150 mg/d of diclofenac. The primary efficacy parameters were the percent of patients improved using a Patients' and Physicians' Global Assessment at endpoint. Gastrointestinal safety was assessed by the incidence of gastrointestinal symptoms and adverse events.RESULTS:Three hundred thirty-five patients (mean age = 72 years) with active osteoarthritis were enrolled. There were no statistically significant differences between the two treatment groups in any of the primary efficacy variables. However, differences between the groups were apparent in the frequency of adverse gastrointestinal events. Two patients in the diclofenac group had evidence of gastrointestinal bleeding and/or ulcer compared with none in the nabumetone group. In addition, significantly more (p < 0.05) patients (4%) receiving diclofenac had alanine transaminase values more than twice the upper limit of normal at endpoint compared with patients receiving nabumetone (0%).CONCLUSIONS:Nabumetone was as effective as diclofenac in the treatment of elderly patients with moderate-to-severe osteoarthritis. However, the gastrointestinal safety profile of nabumetone was superior to that of diclofenac with respect to elevation of liver enzymes.

Objective: The objective of this study was to investigate the renal effects of celecoxib, a cyclooxygenase-2 (COX-2) specific nonsteroidal anti-inflammatory drug (NSAID).

AbstractPurpose: The elderly are at increased risk for gastrointestinal (GI) toxicity during treatment with nonsteroidal anti-inflammatory drugs (NSAID). Previous studies have suggested that nabumetone is associated with fewer perforations, ulcers, and bleeds (PUBs) than older NSAIDs in the general arthritis population. The purpose of this analysis was to evaluate the risk of upper GI PUBs associated with nabumetone and various comparator NSAIDs in elderly patients with osteoarthritis.Methods: Because GI PUBs associated with NSAID use are not common, the results of seven randomized, double-blind studies carried out in the US, Canada, and UK were pooled to compare the safety and efficacy of nabumetone and various comparator NSAIDs in an elderly subset of patients with osteoarthritis (OA). Outpatients with moderate to severe osteoarthritis of the knee or hip presenting to a rheumatologist's practice were eligible for enrolment. All studies had a treatment duration of 3-6 months. These studies were pooled and a retrospective analysis of the frequency of upper GI PUBs for each treatment group was performed. Elderly were defined as age ≥ 65.Results: A total of 2613 patients with OA were treated with nabumetone (1308) or comparator NSAIDs (1305). Of the nabumetone-treated patients, 47% (614/1308) were ≥65 years of age and of the patients treated with comparator NSAIDs, 50% (655/1305) were ≥ 65 years. The raw frequency of PUBs in the elderly population was 0% (0/614) for patients treated with nabumetone and 1.1% (7/655) in patients treated with comparator NSAIDs (p < 0.02 by a Fisher's Exact Test). This was equivalent to 0 in approximately 243.5 patient-years of exposure with nabumetone compared with 7/263.8 or 2.7 per 100 patient-years of exposure with comparator NSAIDs. Six of the seven comparator PUBs were classified as complications and one was an uncomplicated peptic ulcer.Conclusions: In this analysis of PUBs in an elderly population with osteoarthritis, nabumetone use was associated with significantly fewer PUBs and significantly fewer complications than were the comparator NSAIDs used in these studies.

The role of Helicobacter pylori infection in non-steroidal antiinflammatory drugs (NSAIDs) users is controversial.The effect of H. pylori on the gastrointestinal toxicity of NSAIDs might not be the same in all clinical situations.Objective: To determine the role of H. pylori infection in the risk of peptic ulcer bleeding in patients taking low-dose aspirin.Methods: A case-control study of current users of low-dose aspirin (n = 91) admitted because of bleeding peptic ulcer, was carried out.Controls were 106 low-dose aspirin users without gastrointestinal bleeding with similar age, sex and extent (time and dose) of aspirin use to cases.H. pylori infection was determined by either l3C-urea breath test or CagA/VacA serology (western blot) in all cases and controls.Clinical variables were collected by structured data collection.Bivariate and multivariate statistical analyses were performed.Results: H. pylori infection was present in 93.4% of cases and 71.4% of controls and was a risk factor associated with peptic ulcer bleeding.This risk was not dependent on the presence of CagA (+) strains (45.2% -42/93in controls and 53.8% -43/80in cases)(Table ) and was associated with duodenal ulcer bleeding (Adjusted Odds Ratio = 10.3;95% CI: 1.3-79;) but not with gastric ulcer bleeding (Adjusted Odds Ratio = 2.5; 95% CI: 0.72-8.7)(sex,age,alcoholand antisecretory therapy included in the models).Conclusion: H. pylori infection is a risk factor associated with peptic ulcer bleeding in low-dose aspirin users.This risk was especially associated with duodenal ulcer bleeding, but it was not influenced by the infection of CagA positive H. pylori strains.

OBJECTIVE:The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared.BACKGROUND:Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients.METHODS:This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events.RESULTS:A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone.CONCLUSIONS:Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

The purpose of this study was to evaluate the efficacy and safety of four different doses of granisetron when administered as a single intravenous (i.v.) dose for prophylaxis of cisplatin-induced emesis in a multicenter, randomized, parallel-group, double-blind investigation. A total of 353 chemotherapy-naive patients were enrolled, stratified according to cisplatin dose (moderate dose: 50–80 mg/m2,n = 169; high dose: 81–120 mg/m2,n = 184) and randomized to one of four granisetron doses: 5, 10, 20, or 40 µ/kg. Control of emesis was evaluated by the percentages of patients attainingcomplete response (no vomiting or retching, and no rescue medication) andmajor response (≤2 episodes of vomiting or retching, and no rescue medication). Patients were assessed on an inpatient basis for 18–24 h. Safety analyses consisted of adverse events and laboratory parameter changes. Complete response rates over 24 h after chemotherapy were 23%, 48%, 48%, and 44% for granisetron doses of 5, 10, 20, and 40 µg/kg, respectively, in the combined patient population (P=0.011 for linear trend); 29%, 56%, 58%, and 41%, respectively, in the moderate-dose cisplatin stratum (P=0.278 for linear trend); and 18%, 41%, 40%, and 47%, respectively, in the high-dose cisplatin stratum (P = 0.011 for linear trend). Transient headache was the most frequently reported adverse event (19%). There was no evidence of association between increased dose and headache. A single 10-, 20- or 40-µg/kg dose of granisetron is comparably effective in controlling nausea and vomiting associated with moderateor high-dose cisplatin chemotherapy. Granisetron was safe and well tolerated at all doses.

The effect of H-2-receptor antagonists on alcohol absorption appears to vary, depending on testing conditions and subject population. In this crossover study of cimetidine (400 mg b.i.d.) and ranitidine (150 mg b.i.d.), we evaluate alcohol pharmacokinetics in 10 subjects after ingestion of moderate doses (0.5 g/kg) of ethanol under four challenge conditions: (a) a single dose of placebo prior to alcohol ingestion in the morning, (b) a single dose of H-2-antagonist prior to alcohol ingestion in the morning, (c) 14-day chronic dosing with H-2-antagonist prior to alcohol ingestion in the evening, and (d) 28-day chronic dosing with H-2-antagonist prior to alcohol ingestion in the morning. No significant increases were observed for alcohol in the area under the curve (AUC) or C(max). Significant decreases in AUC (16 and 13%) were observed following administration of single- and multiple-dose cimetidine, and a significant decrease in C(max) (14%) was observed following a single dose of ranitidine-all given prior to alcohol ingestion in the morning. These results do not support any clinically meaningful effect of H-2-antagonists on alcohol absorption following ingestion of a moderate dose of ethanol.