Effects of nabumetone compared with naproxen on platelet aggregation in patients with rheumatoid arthritis

Knijff-Dutmer, Ellen A J; Martens, Alexander; Laar, Mart A F J J J van de

doi:10.1136/ard.58.4.257

Cited by 28 publications

(16 citation statements)

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“…23 Other potential benefits of COX-1 inhibition include enhancement of protection against colon carcinogenesis. 24 Thus, nabumetone, with its safety and anti-platelet activity, 25 appears to be an excellent NSAID for use in cancer prevention.…”

Section: Discussionmentioning

confidence: 99%

Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone

2001

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Use of non-steroidal anti-inflammatory drugs (NSAIDs) for chemoprevention of colon cancer has been hindered by their potential gastro-intestinal toxicity. Nabumetone, which is approximately 10 to 36 times safer than conventional NSAIDs, was evaluated in 2 models of experimental colon carcinogenesis. In azoxymethane (AOM)-treated Fisher 344 rats, nabumetone caused dose-dependent inhibition of aberrant crypt foci (ACF), with 750 and 1,500 ppm resulting in 15% and 37% reductions, respectively (p < 0.05). Moreover, complex ACF were reduced by 48% in the latter group. MIN mice studies confirmed the chemopreventive efficacy of nabumetone, with 900 ppm suppressing approximately half of the intestinal tumors. Interestingly, inhibition of intermediate biomarkers in both models was markedly greater in the distal than the proximal bowel. To mechanistically evaluate this regional selectivity, we assessed cyclo-oxygenase-2 (COX-2) expression in the uninvolved mucosa and demonstrated a 3-to 4-fold excess in the distal relative to the proximal bowel in both MIN mice and AOM-treated rats. We then investigated another putative NSAID target, peroxisome proliferator-activated receptor-␦ (PPAR-␦) and demonstrated up-regulation during AOM-induced colonic tumorigenesis. Furthermore, in pre-neoplastic mucosa, there was a 3-fold excess of PPAR-␦ in the distal colon. We demonstrate that nabumetone is an effective protective agent in both experimental models of colon carcinogenesis. The striking distal predilection of nabumetone may be, at least partially, explained by distal bowel over-expression of COX-2 and PPAR-␦. © 2001 Wiley-Liss, Inc.Key words: non-steroidal anti-inflammatory drugs; chemoprevention; colon cancer; nabumetone; azoxymethane Despite significant medical advances in diagnosis and therapy, colorectal malignancies remain the second leading cause of cancer mortality in the United States, 1 underscoring the need for effective chemopreventive strategies. A variety of agents have been purported to protect against colon cancer; of these, the non-steroidal anti-inflammatory drugs (NSAIDs) have demonstrated the greatest promise. 2 The epidemiological and experimental evidence indicates that NSAIDs can reduce the risk of colorectal cancer by up to 50%; 3 however, utilization of NSAIDs for colon-cancer prevention has been hindered by their propensity to cause gastro-intestinal injury. 4 To minimize these untoward effects, novel NSAIDs have been developed with selectivity for cyclo-oxygenase-2 (COX-2), the COX isoform not expressed in normal gastro-intestinal epithelium. 5 COX-2, but not COX-1, is markedly up-regulated early during colon carcinogenesis. 3 Therefore, selective targeting of COX-2 may afford protection against colorectal cancer without the gastro-intestinal toxicity associated with depletion of COX-1-dependent mucosal cytoprotective prostaglandins.Nabumetone, an NSAID in widespread clinical use, has a 7-fold higher affinity for COX-2 than COX-1. 6 Moreover, a meta-analysis indicates that nabumetone is 10 to 36 times s...

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Section: Discussionmentioning

confidence: 99%

Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone

2001

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“…Before its introduction, it was predicted from the mechanism of action that the drug should reduce the incidence of gastrointestinal bleeding [9] but also increase the incidence of thrombosis, compared with non-selective NSAIDs [10][11][12]. Two trials conducted by Merck, 090 [3,13,14] and VIGOR [15], both showed that rofecoxib increased the risk of cardiovascular events significantly.…”

Section: Discussionmentioning

confidence: 99%

Unbalanced reporting of benefits and harms in abstracts on rofecoxib

Jørgensen

Gøtzsche

2010

Eur J Clin Pharmacol

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“…Their effects on platelet-vessel wall function in vivo at anti-inflammatory dosing schedules are not well characterized. Knijff-Dutmer et al reported that treatment with naproxen 500 mg bid for 2 weeks in patients with rheumatoid arthritis resulted in significant inhibition of platelet aggregation ex vivo when compared with nabumetone, but there was no effect on bleeding time [48]. The exact timing of the sampling for platelet aggregation studies in relation to the administration of naproxen was not reported.…”

Section: Smooth Muscle Cellsmentioning

confidence: 92%