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Traditional NSAIDs (traditional + nsaid)
Selected AbstractsNO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Grant D. Stewart Abstract Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1, (HIF-1,) mRNA using RNAi. Nuclear HIF-1, levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1, translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3. © 2008 Wiley-Liss, Inc. [source] The Coxib NSAIDs: Potential Clinical and Pharmacologic Importance in Veterinary MedicineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2005Mary Sarah Bergh Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control acute and chronic pain as well as to manage oncologic and neurologic diseases in human and veterinary patients. Despite ongoing research and efforts to improve the safety and efficacy of existing drugs, adverse effects such as gastrointestinal irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. The true incidence of NSAID-induced adverse effects in animals is unknown, but is likely underestimated, because cats and dogs may be more sensitive than humans to NSAIDs due to alterations in drug metabolism, absorption, and enterohepatic recirculation. NSAIDs produce both analgesia and toxic adverse effects primarily by inhibiting cyclooxygenase (COX), thereby decreasing the production of prostaglandins that signal inflammation and pain as well as mediate physiologic functions such as platelet aggregation, gastric protection, and electrolyte balance in the kidney. The presence of at least 2 COX isoforms may account for variability in NSAID efficacy and toxicity both within and among species. This paper reviews and evaluates the published literature on the safety, pharmacology, uses, and complications of a subclass of COX-1,sparing drugs, the coxibs, in veterinary medicine. Coxibs and other COX-1,sparing drugs provide a clinically useful improvement over traditional NSAIDs, but data are incomplete and more in vivo species-specific, target-tissue, and clinical studies are needed. [source] A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative painACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 5 2004J. Rømsing Background:, We have reviewed the analgesic efficacy of cyclooxygenase-2 (COX-2) inhibitors compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs), different COX-2 inhibitors, and placebo in post-operative pain. Methods:, Randomized controlled trials were evaluated. Outcome measures were pain scores and demand for supplementary analgesia 0,24 h after surgery. Results:, Thirty-three studies were included in which four COX-2 inhibitors, rofecoxib 50 mg, celecoxib 200 and 400 mg, parecoxib 20, 40 and 80 mg, and valdecoxib 10, 20, 40, 80 mg were evaluated. Ten of these studies included 18 comparisons of rofecoxib, celecoxib, or parecoxib with NSAIDs. Rofecoxib 50 mg and parecoxib 40 mg provided analgesic efficacy comparable to that of the NSAIDs in the comparisons, and with a longer duration of action after dental surgery but possibly not after major procedures. Celecoxib 200 mg and parecoxib 20 mg provided less effective pain relief. Four studies included five comparisons of rofecoxib 50 mg with celecoxib 200 and 400 mg. Rofecoxib 50 mg provided superior analgesic effect compared with celecoxib 200 mg. Data on celecoxib 400 mg were too sparse for firm conclusions. Thirty-three studies included 62 comparisons of the four COX-2 inhibitors with placebo and the COX-2 inhibitors significantly decreased post-operative pain. Conclusion:, Rofecoxib 50 mg and parecoxib 40 mg have an equipotent analgesic efficacy relative to traditional NSAIDs in post-operative pain after minor and major surgical procedures, and after dental surgery these COX-2 inhibitors have a longer duration of action. Besides, rofecoxib 50 mg provides superior analgesic effect compared with celecoxib 200 mg. [source] COX-2 inhibitors: complex association with lower risk of hospitalization for gastrointestinal events compared to traditional NSAIDs plus proton pump inhibitors,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 10 2009Michiel W. van der Linden MDPhD Abstract Purpose To compare hospitalization rates for serious upper and lower gastrointestinal (GI) events between chronic and acute users of a traditional non-steroidal anti-inflammatory drugs (tNSAID),+,proton pump inhibitor (PPI) and users of a COX-2 selective inhibitor (Coxib). Methods The PHARMO Record Linkage System, including linked drug-dispensing and hospital records of approximately 3 million individuals in the Netherlands was used. We selected new Coxib or tNSAID users (01/01/2000,31/12/2004) with ,1,year history before the first NSAID dispensing and ,1,year follow-up ending at the first hospitalization for GI event (the outcome), last dispensing, or end of the study period. Chronic users were patients who used any NSAIDs for ,60,days during the first year (n,=,58,770); others were acute users (n,=,538,420). Multivariate analysis was performed by Poisson regression adjusted for gender, age, and duration of follow-up, tNSAID and Coxib dose, NSAID/PPI adherence, use of other gastroprotective agents, anticoagulants, acetaminophen, corticosteroids, and cardiovascular disease. Results The cohort included 23,999 new tNSAIDs,+,PPI users and 25,977 new Coxib users, with main characteristics: mean,±,SD age 58.1,±,15.5 vs. 56.7,±,17.5; female 55.3% vs. 62.2%; duration of treatment (days): 137,±,217 vs. 138,±,179, respectively. Among acute users, adjusted hazard ratios (95% Confidence Interval) were 0.21 (0.14,0.32) for upper and 0.26 (0.16,0.42) for lower GI events, for Coxib versus tNSAIDs,+,PPI users. Among chronic users, these were 0.35 (0.22,0.55) for upper GI and 0.43 (0.25,0.75) for lower GI events. Conclusions Coxib users had significantly lower rates of GI events. Further research should elucidate the possible impact of selection bias. Copyright © 2009 John Wiley & Sons, Ltd. [source] Onset of acute myocardial infarction after use of non-steroidal anti-inflammatory drugs,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2008Tarek A. Hammad MD Abstract Purpose To examine the association between cyclooxygenase-2 (COX-2) selective and traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and incident acute myocardial infarction (AMI), and to address unanswered questions regarding the contour of risk over time. Methods A cohort of new NSAID users aged 40,84 years was followed for the occurrence of first AMI. Data were collected within the General Practice Research Database (GPRD) from 1 January 1997 to 31 December 2004. Results The study population included 1185 AMI events (889 probable and 296 possible) from a cohort of 283,136 patients. After adjustment for demographic and cardiovascular risk factors, the hazard ratio (HR) for AMI was significantly increased for both coxib (2.11, 95% confidence interval (CI) 1.04,4.26) and non-coxib (2.24, 95%CI 1.13,4.42) COX-2 selective NSAIDs when compared to remote exposure to NSAIDs, but was not increased for traditional NSAIDs. Stratifying exposure into the first month of use versus use beyond 1 month, the risk of AMI was increased during the first month of COX-2 selective NSAIDs use, but not later (3.43, 95%CI 1.66,7.07 and 1.88, 95%CI 0.82,4.31, respectively p -value for interaction,=,0.6). Conclusions The results suggest that the use of coxib and non-coxib COX-2 selective NSAIDs was associated with an elevated risk of AMI within the first month of exposure. Recent past exposure to NSAID was not associated with a similar increase in risk. Copyright © 2008 John Wiley & Sons, Ltd. [source] Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleedingARTHRITIS & RHEUMATISM, Issue 6 2010Elvira L. Massó González Objective Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82,5.31) for traditional NSAIDs and 1.88 (95% CI 0.96,3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17,3.33]), rofecoxib (2.12 [95% CI 1.59,2.84]), aceclofenac (1.44 [95% CI 0.65,3.2]), and celecoxib (1.42 [95% CI 0.85,2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87,36.04]) and piroxicam (9.94 [95% CI 5.99,16.50). Estimated RRs were 5.63 (95% CI 3.83,8.28) for naproxen, 5.57 (95% CI 3.94,7.87) for ketoprofen, 5.40 (95% CI 4.16,7.00) for indomethacin, 4.15 (95% CI 2.59,6.64) for meloxicam, and 3.98 (95% CI 3.36,4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. [source] Underutilization of gastroprotective measures in patients receiving nonsteroidal antiinflammatory drugsARTHRITIS & RHEUMATISM, Issue 8 2002Walter Smalley Objective To determine the frequency of use of recommended gastroprotective strategies in a cohort of patients receiving recurrent treatment with nonsteroidal antiinflammatory drugs (NSAIDs). Methods A cross-sectional study was performed using administrative data from the Tennessee Medicaid (TennCare) program. The study population consisted of 76,765 recurrent recipients of NSAIDs (NSAID users), comprising 24% of the 319,402 persons ages 50 years or older enrolled in the TennCare program from January 1999 through June 2000. Frequency of use of either of 2 recommended gastroprotective strategies, involving either traditional NSAIDs combined with recommended anti-ulcer cotherapy or use of a selective cyclooxygenase 2,inhibiting drug (coxib), was measured and categorized by risk for ulcer complication. Results Among this cohort of recurrent NSAID users, 16% received 1 of the 2 recommended gastroprotective therapies: 10% received traditional NSAIDs along with antiulcer drugs at the recommended doses and 6% received coxibs. Among those patients with ,2 risk factors for ulcer complications (age 75 years or older, peptic ulcer or gastrointestinal bleeding in the past year, or concurrent use of oral anticoagulants or corticosteroids), 30% received such gastroprotective therapy. Conclusion Use of recommended strategies to decrease ulcer complications in vulnerable populations is relatively uncommon. [source] | ||||||||||