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Use of Selective Cyclooxygenase-2 Inhibitors, Other Analgesics, and Risk of Glioma.

ABSTRACT: Selective cyclooxygenase-2 (COX-2) inhibitors are analgesic, antipyretic, and anti-inflammatory drugs. They have been found to inhibit the development of glioma in laboratory investigations. Whether these drugs reduce the risk of glioma incidence in humans is unknown.We conducted a matched case-control analysis using the U.K.-based Clinical Practice Research Datalink (CPRD). We identified 2,469 cases matched to 24,690 controls on age, sex, calendar time, general practice, and number of years of active history in the CPRD prior to the index date. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) of glioma in relation to use of selective COX-2 inhibitors, adjusted for several confounding variables.Use of selective COX-2 inhibitors was unrelated to risk of glioma (adjusted OR for 1-9 versus 0 prescriptions = 1.02; 95% CI = 0.92-1.13, 10-29 versus 0 prescriptions = 1.01; 95% CI = 0.80-1.28, ≥30 versus 0 prescriptions = 1.16; 95% CI = 0.86-1.55). Trends for increasing numbers of prescriptions for other non-steroidal anti-inflammatory drugs (NSAIDs), and non-NSAID analgesics were also not associated with glioma risk.Further epidemiologic studies are needed to confirm the null relation of use of selective COX-2 inhibitors to glioma risk and to explain the discrepancy between laboratory investigations and our observational study.Use of selective COX-2 inhibitors is unrelated to glioma risk.

SUBMITTER: Seliger C

PROVIDER: S-EPMC4752241 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.

Project description:We report the design, synthesis, and evaluation of a series of harmaline analogs as selective inhibitors of 2-arachidonylglycerol (2-AG) oxygenation over arachidonic acid (AA) oxygenation by purified cyclooxygenase-2 (COX-2). A fused tricyclic harmaline analog containing a CH3O substituent at C-6 and a CH3 group at the C-1 position of 4,9-dihydro-3H-pyrido[3,4-b]indole (compound 3) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC50 of 0.022 μM as compared to >1 μM for AA. The 2.66 Å resolution crystal complex of COX-2 with compound 3 revealed that this series of tricyclic indoles binds in the cyclooxygenase channel by flipping the side chain of L531 toward the dimer interface. This novel tricyclic indole series provides the foundation for the development of promising substrate-selective molecules capable of increasing endocannabinoid (EC) levels in the brain to offer new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders.

| S-EPMC7549255 | biostudies-literature

Defects in mouse nephrogenesis induced by selective and non-selective cyclooxygenase-2 inhibitors.

Project description:BACKGROUND AND PURPOSE: Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described. EXPERIMENTAL APPROACH: We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21. KEY RESULTS: All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE(2) synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2(-/-) mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology. CONCLUSIONS AND IMPLICATIONS: Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.

| S-EPMC3130940 | biostudies-literature

Propyphenazone-based analogues as prodrugs and selective cyclooxygenase-2 inhibitors.

Project description:Improving the gastrointestinal safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) is an important goal. Herein, we report two strategies, using the nonacidic propyphenazone structure, with potential to overcome the side effects of NSAIDs. Propyphenazone was employed to temporarily mask the free acid group of the widely used NSAIDs ibuprofen, diclofenac, and ketoprofen to develop three mutual prodrugs hypothesized to have minimal GI irritation. The three prodrugs exhibit in vivo anti-inflammatory and analgesic activities with improved potency over each parent drug when compared to a nonhydrolyzable control betahistine-propyphenazone (BET-MP). Additionally, ANT-MP formed by the irreversible coupling of propyphenazone and 4-aminoantipyrine, displayed exceptional COXII selectivity (COXII IC50 of 0.97 ± 0.04 ?M, compared to no observed inhibition of COXI at 160 ?M). Inhibition of COXII suppresses inflammatory diseases without affecting COXI-mediated GI tract events. ANT-MP exhibited maximal analgesic effect when tested in vivo in an abdominal writhing assay (100% protection) and its anti-inflammatory activity showed a peak at 2 h in a carrageenan-induced paw edema model. Its unique selectivity toward the COXII enzyme was investigated using molecular modeling techniques.

| S-EPMC4160749 | biostudies-literature

Ortho-carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors.

Project description:A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.

| S-EPMC3408963 | biostudies-literature

Differential effects of selective and non-selective cyclooxygenase inhibitors on fecal microbiota in adult horses.

Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used in both veterinary and human medicine. Gastrointestinal injury is a frequent adverse event associated with NSAID use and evidence suggests that NSAIDs induce gastrointestinal microbial imbalance (i.e., dysbiosis) in both animals and people. It is unknown, however, whether cyclooxygenase (COX)-2-selective NSAIDs induce dysbiosis, or if this phenomenon occurs in horses administered any class of NSAIDs. Therefore, our objectives were to determine whether the composition and diversity of the fecal microbiota of adult horses were altered by NSAID use, and whether these effects differed between non-selective and COX-2-selective NSAIDs. Twenty-five adult horses were randomly assigned to 1 of 3 groups: control (n = 5); phenylbutazone (n = 10); or, firocoxib (n = 10). Treatments were administered for 10 days. Fecal samples were collected every 5 days for 25 days. DNA was extracted from feces and the 16S rRNA gene amplified and sequenced to determine the composition of the microbiota and the inferred metagenome. While the fecal microbiota profile of the control group remained stable over time, the phenylbutazone and firocoxib groups had decreased diversity, and alteration of their microbiota profiles was most pronounced at day 10. Similarly, there were clear alterations of the inferred metagenome at day 10 compared to all other days, indicating that use of both non-selective and selective COX inhibitors resulted in temporary alterations of the fecal microbiota and inferred metagenome. Dysbiosis associated with NSAID administration is clinically relevant because dysbiosis has been associated with several important diseases of horses including abdominal pain (colic), colitis, enteric infections, and laminitis.

| S-EPMC6107168 | biostudies-literature

Protective effects of selective and non-selective cyclooxygenase inhibitors in an animal model of chronic stress.

Project description:Cyclooxygenase isoenzyme is known to be expressed in different regions of brain, and is mainly used for the treatment of pain and inflammation. Recently, it is proposed that cyclooxygenase isoenzyme may also play a key role in the pathophysiology of various brain-related disorders. The present study was aimed to explore the protective effect of cyclooxygenase inhibitors on stress by using an animal model of chronic stress.The animals were forced to swim individually for a period of 6 min every day for 15 d. Then, the behavior (locomotor activity, anxiety and memory) and biochemical (lipid peroxidation, nitrite level, reduced glutathione, and catalase) alterations were assessed.Forced swimming for 15 d caused impaired locomotor activity, anxiety-like behavior and decreased percentage of memory retention, as compared to naive mice (without chronic fatigue treatment). Biochemical analysis revealed significant increases in lipid peroxidation and nitrite level, while levels of reduced glutathione and catalase activity were both decreased. Chronic treatment with naproxen (14 mg/kg, i.p.), rofecoxib (5 mg/kg, i.p.), meloxicam (5 mg/kg, i.p.), nimesulide (5 mg/kg, i.p.) and valdecoxib (10 mg/kg, i.p.) significantly attenuated these behavioral and biochemical (oxidative damage) alterations in chronic-stressed mice.The cyclooxygenase inhibitors could be used in the management of chronic fatigue-like conditions.

| S-EPMC5560377 | biostudies-other

Prescriptions for selective cyclooxygenase-2 inhibitors, non-selective non-steroidal anti-inflammatory drugs, and risk of breast cancer in a population-based case-control study.

Project description:IntroductionNon-steroidal anti-inflammatory drugs (NSAIDs) prevent the growth of mammary tumours in animal models. Two population-based case-control studies suggest a reduced risk of breast cancer associated with selective cyclooxygenase-2 (sCox-2) inhibitor use, but data regarding the association between breast cancer occurrence and use of non-selective NSAIDs are conflicting.MethodsWe conducted a population-based case-control study using Danish healthcare databases to examine if use of NSAIDs, including sCox-2 inhibitors, was associated with a reduced risk of breast cancer. We included 8,195 incident breast cancer cases diagnosed in 1991 through 2006 and 81,950 population controls.ResultsOverall, we found no reduced breast cancer risk in ever users (>2 prescriptions) of sCox-2 inhibitors (odds ratio (OR) = 1.08, 95% confidence interval (95% CI) = 0.99, 1.18), aspirin (OR = 0.98, 95% CI = 0.90-1.07), or non-selective NSAIDs OR = 1.04, (95% CI = 0.98, 1.10)). Recent use (>2 prescriptions within two years of index date) of sCox-2 inhibitors, aspirin, or non-selective NSAIDs was likewise not associated with breast cancer risk (Ors = 1.06 (95% CI = 0.96, 1.18), 0.96 (95% CI = 0.87, 1.06) and 0.99 (95% CI = 0.85, 1.16), respectively). Risk estimates by duration (<10, 10 to 15, 15+ years) or intensity (low/medium/high) of NSAID use were also close to unity. Regardless of intensity, shorter or long-term NSAID use was not significantly associated with breast cancer risk.ConclusionsOverall, we found no compelling evidence of a reduced risk of breast cancer associated with use of sCox-2 inhibitors, aspirin, or non-selective NSAIDs.

| S-EPMC2879557 | biostudies-literature

Cyclooxygenase inhibitors use is associated with reduced risk of esophageal adenocarcinoma in patients with Barrett's esophagus: a meta-analysis.

Project description:BackgroundEsophageal adenocarcinoma (EAC) has high mortality and is increasing in incidence. Barrett's esophagus (BE) increases the risk for EAC. Studies have reported inconsistent findings on the association between use of cyclooxygenase (COX) inhibitors and the risk of neoplastic progression in BE patients. Therefore, we performed a meta-analysis to investigate this association.MethodsA meta-analysis was undertaken among a total of 9 observational studies using fixed- and random-effects models, comprising 5446 participants; 605 had EAC or high-grade dysplasia (HGD).ResultsOverall, COX inhibitors use was associated with a reduced risk of EAC/HGD among BE patients (relative risk (RR)=0.64, 95% confidence interval (CI)=0.53-0.77). Aspirin use also reduced the risk of EAC/HGD (RR=0.63, 95% CI=0.43-0.94), as well as non-aspirin COX inhibitors (RR=0.50, 95% CI=0.32-0.78). The chemopreventive effect seemed to be independent of duration response.ConclusionsCyclooxygenase inhibitors use is associated with a reduced risk of developing EAC in patients with BE. Both low-dose aspirin and non-aspirin COX inhibitors are associated with a reduced risk of neoplasia. More well-designed randomised controlled trials are needed to increase our understanding of the chemopreventive effect of COX inhibitors.

| S-EPMC4007227 | biostudies-literature

Differential effects of selective cyclooxygenase-2 inhibitors on vascular smooth muscle ion channels may account for differences in cardiovascular risk profiles.

Project description:Celecoxib, rofecoxib, and diclofenac are clinically used cyclooxygenase-2 (COX-2) inhibitors, which have been under intense scrutiny because long-term rofecoxib (Vioxx; Merck, Whitehouse Station, NJ) treatment was found to increase the risk of adverse cardiovascular events. A differential risk profile for these drugs has emerged, but the underlying mechanisms have not been fully elucidated. We investigated the effects of celecoxib, rofecoxib, and diclofenac on ionic currents and calcium signaling in vascular smooth muscle cells (VSMCs) using patch-clamp techniques and fura-2 fluorescence and on arterial constriction using pressure myography. Celecoxib, but not rofecoxib or diclofenac, dramatically enhanced KCNQ (K(v)7) potassium currents and suppressed L-type voltage-sensitive calcium currents in A7r5 rat aortic smooth muscle cells (native KCNQ currents or overexpressed human KCNQ5 currents) and freshly isolated rat mesenteric artery myocytes. The effects of celecoxib were concentration-dependent within the therapeutic concentration range, and were reversed on washout. Celecoxib, but not rofecoxib, also inhibited calcium responses to vasopressin in A7r5 cells and dilated intact or endothelium-denuded rat mesenteric arteries. A celecoxib analog, 2,5-dimethyl-celecoxib, which does not inhibit COX-2, mimicked celecoxib in its enhancement of vascular KCNQ5 currents, suppression of L-type calcium currents, and vasodilation. We conclude that celecoxib inhibits calcium responses in VSMCs by enhancing KCNQ5 currents and suppressing L-type calcium currents, which ultimately reduces vascular tone. These effects are independent of its COX-2 inhibitory actions and may explain the differential risk of cardiovascular events in patients taking different drugs of this class.

| S-EPMC2774994 | biostudies-literature

Cyclooxygenase-1-selective inhibitors based on the (E)-2'-des-methyl-sulindac sulfide scaffold.

Project description:Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

| S-EPMC3297362 | biostudies-literature

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