- Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis. [Review]
- DADrugs Aging 2019; 36(Suppl 1):25-44
- CONCLUSIONS: In our analysis, COX-2 inhibitors were associated with an increased risk of upper gastrointestinal AEs, especially abdominal pain. We also found an increased risk of cardiovascular AEs with COX-2 inhibitors, namely hypertension, heart failure and edema.
- Lack of Small Intestinal Dysbiosis Following Long-Term Selective Inhibition of Cyclooxygenase-2 by Rofecoxib in the Rat. [Journal Article]
- CCells 2019 Mar 15; 8(3)
- Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cau…
Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.
- Cyclooxygenase-2 is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404. [Journal Article]
- JAJ Alzheimers Dis 2019; 68(3):1095-1111
- Alzheimer's disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrate…
Alzheimer's disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.
- Impact of drugs on venous thromboembolism risk in surgical patients. [Review]
- EJEur J Clin Pharmacol 2019; 75(6):751-767
- CONCLUSIONS: Increased monitoring for VTE is therefore advisable in surgical patients and those receiving antipsychotics, antidepressants, diuretics, or analgesics.
- Pharmacologically pertinent period of effect (PPPE). [Journal Article]
- PDPharmacoepidemiol Drug Saf 2019 Jan 09
- CONCLUSIONS: The 50 mg observational studies, looking at current exposure, correctively identified the almost immediate increase in risk evident in the VIGOR Kaplan-Meier curves. The absence of an immediate increase in risk shown by the APPROVE trial was also correctively identified by most observational 25 mg studies. To our knowledge no observational study was done on the long-term cardiac toxicity of the 25-mg dose. It would thus appear that the two doses of rofecoxib have different PPPEs.
- Differences in cardiovascular safety with non-steroidal anti-inflammatory drug therapy-A nationwide study in patients with osteoarthritis. [Journal Article]
- BCBasic Clin Pharmacol Toxicol 2019; 124(5):629-641
- Osteoarthritis (OA) and the non-steroidal anti-inflammatory drugs (NSAIDs) used to relieve OA-associated pain have been linked independently to increased cardiovascular risk. We examined the risk of …
Osteoarthritis (OA) and the non-steroidal anti-inflammatory drugs (NSAIDs) used to relieve OA-associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged ≥18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533 502 patients included, 64.3% received NSAIDs and 38 226 (7.2%) experienced a cardiovascular event during follow-up. Compared with non-use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 (95% confidence interval, 1.74-2.08); celecoxib, 1.47 (1.34-1.62); diclofenac, 1.44 (1.36-1.54); ibuprofen, 1.20 (1.15-1.25); and naproxen, 1.20 (1.04-1.39). Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs: 0.81 [CI: 0.74-0.90]) and naproxen (HRs: 0.81 [0.68-0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low-dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs: 1.12 (1.07-1.19) and 1.16 (0.92-1.42), respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief.
- Beware of on-treatment safety analyses. [Journal Article]
- CTClin Trials 2019; 16(1):63-70
- CONCLUSIONS: For major safety outcomes in long-term clinical trials, intention-to-treat analysis should be performed in the framework of benefit-risk evaluation. More generally, analyses of safety should be tailored to the specific question being asked with the specific study design under consideration. On-treatment analyses are subject to bias; however, the direction of that bias is not necessarily clear.
- α-Tocopherol Potentiates the Cervical Resistance Decreasing Effects of COX Inhibitors in Pregnant Rats: The Putative Role of Cyclooxygenase-2 Inhibition. [Journal Article]
- JPJ Pharmacol Exp Ther 2019; 368(2):292-298
- Vitamin E and their analogs as antioxidant and lipid-soluble compounds can have diverse effects on the physiologic processes. By binding to receptors and enzymes, they may modify the action of drugs.…
Vitamin E and their analogs as antioxidant and lipid-soluble compounds can have diverse effects on the physiologic processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that α-tocopherol succinate modifies the effects of β 2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how α-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of nonpregnant and 22 day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro. α-Tocopherol-succinate (10-7 M) was used, whereas the COX-nonselective diclofenac (10-6 M), the COX-2-selective rofecoxib (10-6 M), and the COX-1-selective SC-560 (10-6 M) were applied as inhibitors. The COX activities of the cervices were measured by enzyme immunoassay. The modifying effect of single doses of COX inhibitors and tocopherol on the onset of labor was investigated in vivo. The cervical resistance of nonpregnant samples was not changed by either α-tocopherol or COX inhibitors. On pregnant cervices, tocopherol, diclofenac, or rofecoxib pretreatment decreased cervical resistance that was further reduced by COX inhibitors after pretreatment with tocopherol. α-Tocopherol elicited a significant COX-2 enzyme inhibition in cervical samples from pregnant rats. By coadministration of tocopherol and rofecoxib, the parturition was initiated earlier than in the other groups. It is supposed that COXs play a significant role not only in cervical ripening, but also in the contraction of the cervical smooth muscle a few hours before parturition. This latter action may be developed by COX-2-liberated prostaglandins.
- Gastrointestinal safety of coxibs: systematic review and meta-analysis of observational studies on selective inhibitors of cyclo-oxygenase 2. [Review]
- FCFundam Clin Pharmacol 2019; 33(2):134-147
- Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data…
Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65 years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.
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- Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project. [Journal Article]
- PlosPLoS One 2018; 13(11):e0204746
- CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.