Marked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2

Fries, Susanne; Großer, Tilo; Price, Thomas S.; Lawson, John A.; Kapoor, Shiv; DeMarco, Susan; Pletcher, Mathew T.; Wiltshire, Tim; FitzGerald, Garret A.

doi:10.1053/j.gastro.2005.10.002

Cited by 129 publications

(140 citation statements)

References 44 publications

(62 reference statements)

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“…Rofecoxib induced anti-inflammatory and analgesic effects act not merely through inhibition of COX-2 activity but also involve annexin and cytokine signaling pathways ( Figure 5). Moreover, given the wide inter-individual variability in response to the treatment with tNSAIDs and coxibs in clinical observations Fries et al, 2006), our findings suggest that besides the influence of genetic variability in cytokine gene polymorphisms, the counter-balance between pro-inflammatory and anti-inflammatory mediators induced by COX-2 inhibition may also play a critical role in their anti-inflammatory and analgesic effects as well as their adverse effects. Gene expression profile induced by acute inflammation and inhibition of cyclooxygenase in a clinical model of tissue injury.…”

Section: Rofecoxib Modulates Both Pro-and Anti-inflammatory Mediatorsmentioning

confidence: 81%

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

Wang¹,

Hamza

et al. 2007

Pain

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New insights into the biological properties of cyclooxygenase-2 (COX-2) and its response pathway challenge the hypothesis that COX-2 is simply pro-inflammatory and inhibition of COX-2 solely prevents the development of inflammation and ameliorates inflammatory pain. The present study performed a comprehensive analysis of gene/protein expression induced by a selective inhibitor of COX-2, rofecoxib, compared with a non-selective COX inhibitor, ibuprofen, and placebo in a clinical model of acute inflammatory pain (the surgical extraction of impacted third molars) using microarray analysis followed by quantitative RT-PCR verification and Western blotting. Inhibition of COX-2 modulated gene expression related to inflammation and pain, the arachidonic acid pathway, apoptosis/angiogenesis, cell adhesion and signal transduction. Compared to placebo, rofecoxib treatment increased the gene expression of ANXA3 (annexin 3), SOD2 (superoxide dismutase 2), SOCS3 (suppressor of cytokine signaling 3) and IL1RN (IL1 receptor antagonist) which are associated with inhibition of phospholipase A2 and suppression of cytokine signaling cascades, respectively. Both rofecoxib and ibuprofen treatment increased the gene expression of the proinflammatory mediators, IL6 and CCL2 (chemokine C-C motif ligand 2), following tissue injury compared to the placebo treatment. These results indicate a complex role for COX-2 in the inflammatory cascade in addition to the well-characterized COX-dependent pathway, as multiple pathways are also involved in rofecoxib-induced anti-inflammatory and analgesic effects at the gene expression level. These findings may also suggest an alternative hypothesis for the adverse effects attributed to selective inhibition of COX-2.

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Section: Rofecoxib Modulates Both Pro-and Anti-inflammatory Mediatorsmentioning

confidence: 81%

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

Wang¹,

Hamza

et al. 2007

Pain

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“…Different individuals respond differently to a given COX-2 inhibitor, but more than 2% of the individuals in the polyp prevention trials experienced significant reduction in PGI 2 production. 107 Does the low incidence of toxicity have a statistical or biological basis; i.e., would everyone who experiences COX-2 inhibition eventually develop cardiovascular toxicity or do other factors collaborate with COX-2 inhibition to cause the side effects? Neither explanation can be ruled out at this time, but there are data to support a multifactorial basis for cardiovascular toxicity.…”

Section: Iii4 Diaryl Heterocycles (Sulfonamides and Methyl Sulfones)mentioning

confidence: 99%

Structural and Functional Basis of Cyclooxygenase Inhibition

2007

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“…For example, one study showed that the level of PTGS2 expression and the degree of pain relief experienced upon treatment with rofecoxib and ibuprofen varied by allele group. 7 Furthermore, there is evidence that several genetic variants in the PTGS1 gene alter the metabolism of arachidonic acid to Prostaglandin H2 (PGH 2 ); the precursor to prostacyclin, thromboxane and several other prostaglandins. 9 Moreover, inhibition of PGH 2 by aspirin varied by allele group at two SNPs located within the PTGS1 gene.…”

Section: Candidate Gene Selectionmentioning

confidence: 99%

“…[5][6][7] Therefore, it is plausible that the presence of one or more genetic polymorphisms may create an environment in which a COX-2 inhibitor will trigger cardiovascular events leading to a myocardial infarction or stroke.…”

Section: Introductionmentioning

confidence: 99%

“…Nous avons observé des interactions gène-médicament statistiquement significatives entre l'exposition aux AINS et 16 PNS. De ce nombre, quatre interactions se sont accentuées et sont demeurées significatives dans un sousgroupe recevant des coxibs incluant un PNS du gène de la Protéine C réactive (PCR) (OU=3,6; 95 % Intervalle de confiance [IC], 1,6 -7,9; P=0,001), deux PNS du gène de la cyclooxygénase-1 (COX-1) (OU=6,9; 95 % IC, 1,7;P=0,02 et OU=6,9;95 % IC,1,6; P=0,02) un PNS du gène de la Klotho (OU=2,3;95 % IC,1,9;P=0,002). …”

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Genetic Polymorphisms and the Cardiovascular Risk of Non-Steroidal Anti-Inflammatory Drugs

Germaine

Bogaty

Boyer

et al. 2010

The American Journal of Cardiology

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The cardiovascular safety of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) is of concern, although the majority of users remain free of adverse outcomes. A gene-drug interaction may contribute to the variation in individual response to NSAIDs.In a case-only study of 460 patients selected from a cohort admitted for an acute coronary syndrome we genotyped 115 single nucleotide polymorphisms (SNPs). We observed statistically significant gene-drug interactions between NSAID exposure and 16SNPs. Of these, four interactions strengthened and remained significant in a COX-2 subgroup including a SNP in the C-Reactive Protein (CRP) gene (OR=3.6; 95%Confidence Interval [CI], 1.6 -7.9; P=0.001), two SNPs in the cyclooxygenase-1 (COX-1) gene (OR=6.9; 95% CI, 1. P=0.02 and OR=6.9; 95% CI, P=0.02) and one SNP in the Klotho gene (OR=2.3; 95% CI, 1.4-3.9; P=0.002).Genetic polymorphisms within the COX-1, CRP and Klotho genes are candidates for gene-drug interactions influencing the cardiovascular outcomes of users of NSAIDs.These findings suggest that genetic susceptibility may contribute to coronary instability in some users of this class of drugs.iv Contribution of AuthorsThis thesis includes the text of a manuscript that will be submitted for publication. I (Christine St.Germaine) wrote the application for funding for the MUHC pilot project competition, the ethics protocol, the thesis, and the manuscript. I used the existing database and the suggested study design to develop the study methods. I also reviewed the literature and suggested a list of possible candidate genes to study. I was primarily responsible for the statistical analysis conducted in SAS Dr. James Brophy was primarily responsible for the supervision of this project. He proposed the research question and suggested the case-only study design. He provided comments, suggestions and revisions on the application for funding to the MUHC pilot project competition, all chapters in the thesis and drafts of the manuscript.Dr. Jamie Engert shared his knowledge and guidance in genetics. He answered questions regarding genetics databases and software used in this thesis. He contributed to the selection of candidate genes and provided advice on the methods of statistical analysis for this genetic study as well as comments, suggestions and revisions for the thesis and the manuscript.Dr. Hanley attended committee meetings and provided statistical advice. He also offered comments and suggestions to improve the quality of the manuscript and the thesis.Dr. Peter Bogaty provided the genetic samples and database of patient information used in this study. Luce Boyer assisted in the retrieval and delivery of genetic samples.All authors contributed to the interpretation of the results of this study.ix

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Marked Interindividual Variability in the Response to Selective Inhibitors of Cyclooxygenase-2

Cited by 129 publications

References 44 publications

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain

Structural and Functional Basis of Cyclooxygenase Inhibition

Genetic Polymorphisms and the Cardiovascular Risk of Non-Steroidal Anti-Inflammatory Drugs

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