Antagonism of thromboxane receptors by diclofenac and lumiracoxib

Selg, Ewa; Buccellati, Carola; Andersson, Margareta; Rovati, G. Enrico; Ezinga, M; Sala, Angelo; Larsson, A-K; Ambrosio, Emilio; Låstbom, Lena; Capra, Valérie; Dahlén, Barbro; Ryrfeldt, Åke; Folco, Giancarlo; Se, Dahlén

doi:10.1038/sj.bjp.0707518

Cited by 31 publications

(10 citation statements)

References 39 publications

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“…It has been reported that lumiracoxib is not only a COX‐2 inhibitor, as it also exhibits activity as a thromboxane receptor antagonist in the micromolar concentration range (Selg et al. , 2007).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase‐2, in rats

Vásquez-Bahena

Salazar-Morales

Ortiz

et al. 2010

British J Pharmacology

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Background and purpose:This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats. Experimental approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg -1 of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg -1 oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI. Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT = LT0/(1 + MED). LT0 is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 mg·mL -1. Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase‐2, in rats

Vásquez-Bahena

Salazar-Morales

Ortiz

et al. 2010

British J Pharmacology

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“…The demonstration by Selg et al . that both a tNSAID (e.g., diclofenac) and a highly selective COXIB (e.g., lumiracoxib) possess the previously undescribed pharmacological profile of competitive antagonism at the TP receptor may provide the basis to hypothesize a novel class of safer NSAIDs (third generation) and to plan highly innovative studies of structure‐activity relationship, chemical synthesis, and pharmacological investigations …”

Section: Cyclooxygenase Products and Cardiovascular Pathophysiologymentioning

confidence: 99%

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Capra

Bäck

Barbieri

et al. 2012

Medicinal Research Reviews

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Eicosanoids are biologically active lipids in both physiologic and pathophysiologic situations. These mediators rapidly generate at sites of inflammation and act through specific receptors that following the generation of a signal transduction cascade, lead to coordinated cellular responses to specific stimuli. Prostanoids, that is, prostaglandins and thromboxane A(2), are active products of the cyclooxygenase pathway, while leukotrienes and lipoxins derive from the lipoxygenase pathway. In addition, a complex family of prostaglandin isomers called isoprostanes is derived as free-radical products of oxidative metabolism. While there is a wide consensus on the importance of the balance between proaggregating (thromboxane A(2)) and antiaggregating (prostacyclin) cyclooxygenase products in cardiovascular homeostasis, an increasing body of evidence suggests a key role also for other eicosanoids generated by lipoxygenases, epoxygenases, and nonenzymatic pathways in cardiovascular diseases. This intricate network of lipid mediators is unique considering that from a single precursor, arachidonic acid, may derive an array of bioproducts that interact within each other synergizing or, more often, behaving as functional antagonists.

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“…Ramatroban, a TP antagonist recognized to inhibit platelet aggregation induced by collagen and U46619 [20] . Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), concentration dependently and selectively inhibited TP mediated contraction in smooth muscles as well as human platelet aggregation [21] . The fourth compound we tested was L-670596, a potent TP antagonist in human platelets and shown to inhibit contraction in guinea pig tracheal rings in a concentration dependent manner [22] .…”

Section: Introductionmentioning

confidence: 99%

Inverse Agonism of SQ 29,548 and Ramatroban on Thromboxane A2 Receptor

et al. 2014

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G protein-coupled receptors (GPCRs) show some level of basal activity even in the absence of an agonist, a phenomenon referred to as constitutive activity. Such constitutive activity in GPCRs is known to have important pathophysiological roles in human disease. The thromboxane A2 receptor (TP) is a GPCR that promotes thrombosis in response to binding of the prostanoid, thromboxane A2. TP dysfunction is widely implicated in pathophysiological conditions such as bleeding disorders, hypertension and cardiovascular disease. Recently, we reported the characterization of a few constitutively active mutants (CAMs) in TP, including a genetic variant A160T. Using these CAMs as reporters, we now test the inverse agonist properties of known antagonists of TP, SQ 29,548, Ramatroban, L-670596 and Diclofenac, in HEK293T cells. Interestingly, SQ 29,548 reduced the basal activity of both, WT-TP and the CAMs while Ramatroban was able to reduce the basal activity of only the CAMs. Diclofenac and L-670596 showed no statistically significant reduction in basal activity of WT-TP or CAMs. To investigate the role of these compounds on human platelet function, we tested their effects on human megakaryocyte based system for platelet activation. Both SQ 29,548 and Ramatroban reduced the platelet hyperactivity of the A160T genetic variant. Taken together, our results suggest that SQ 29,548 and Ramatroban are inverse agonists for TP, whereas, L-670596 and Diclofenac are neutral antagonists. Our findings have important therapeutic applications in the treatment of TP mediated pathophysiological conditions.

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Antagonism of thromboxane receptors by diclofenac and lumiracoxib

Cited by 31 publications

References 39 publications

Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase‐2, in rats

Pharmacokinetic–pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase‐2, in rats

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

Inverse Agonism of SQ 29,548 and Ramatroban on Thromboxane A2 Receptor

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