Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state

Tegeder, Irmgard; Lötsch, Jörn; Krebs, Sabine; Muth-Selbach, Uta; Brune, Kay; Geißlinger, Gerd

doi:10.1016/s0009-9236(99)70073-1

Cited by 44 publications

(37 citation statements)

References 36 publications

(46 reference statements)

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“…10 As a matter of the fact, such a dramatic loss in COX inhibitory potency and a drop in selectivity under the HWB assay conditions are common to other selective COX-2 inhibitors, such as valdecoxib, 31,32 etoricoxib, 31,32 lumiracoxib, 33 and rofecoxib, 34,35 as well as tNSAIDs such as nimesulide 16,31 and meloxicam. 36,37 It should be pointed out that, according to the test, 10a, 10c, and 11c exhibited an affinity for COX-2 5-10-fold higher than that for COX-1, which should translate clinically into an acceptable GI safety, and allowing for a sufficient prostacyclin generation that should mitigate the CV effects showed by overly selective COX-2 inhibitors, as previously discussed.…”

Section: Resultsmentioning

confidence: 82%

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

et al. 2009

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A new generation of selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) was developed to circumvent the major side effects of cyclooxygenase-1 (COX-1) and COX-2 inhibitors (stomach ulceration and nephrotoxicity). As a consequence, coxibs are extremely valuable in treating acute and chronic inflammatory conditions. However, the use of coxibs, such as rofecoxib (Vioxx), was discontinued because of the high risk of cardiovascular adverse events. More recent clinical findings highlighted how the cardiovascular toxicity of coxibs could be mitigated by an appropriate COX-1 versus COX-2 selectivity. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, selective for COX-2. Here, we describe the synthesis of new 1,5-diarylpyrroles along with their inhibitory effects in vitro, ex vivo, and in vivo toward COX isoenzymes and their analgesic activity. Isopropyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrrole-3-acetate (10a), a representative member of the series, was selected for pharmacokinetic and metabolic studies.

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Section: Resultsmentioning

confidence: 82%

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

et al. 2009

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“…It should be noted that diclofenac and lumiracoxib have a relatively low risk of gastrointestinal complications (Henry et al, 1996). This reduced risk with diclofenac and lumiracoxib was associated with the preferential or complete inhibition of COX-2 at therapeutic doses, respectively (Tegeder et al, 1999;Brune, 2007). It remains to be further investigated whether the low Fig.…”

Section: Downloaded Frommentioning

confidence: 97%

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

Mandery¹,

Bujok²,

Schmidt³

et al. 2009

J Pharmacol Exp Ther

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The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E 2 with IC 50 values of 6.2 Ϯ 1.2 and 3.1 Ϯ 1.2 M. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE 2 transport by 162.7 Ϯ 13.9, 77.2 Ϯ 3.6, and 32.3 Ϯ 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

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“…Meloxicam was also more potent in reducing edema of the inflamed rat paw than indomethacin, piroxicam, diclofenac, or naproxen (Engelhardt et al, 1995;Engelhardt, 1996) and produced analgesia in rat and dog models of inflammatory pain (Cross et al, 1997;Laird et al, 1997;Santos et al, 1998). At therapeutic doses of 7.5 or 15 mg, meloxicam did not reduce platelet aggregation or prolong bleeding time ex vivo (Stichtenoth et al, 1997;De Meijer et al, 1999;Panara et al, 1999;Tegeder et al, 1999), although thromboxane formation by platelets was inhibited by 35% after 15 mg of meloxicam. This demonstrated the low inhibitory activity against COX-1 of meloxicam in vivo.…”

Section: A Treatment Of Inflammatory Diseasesmentioning

confidence: 99%

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

2004

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Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state

Cited by 44 publications

References 36 publications

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

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