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Dúvidas [email protected] Arquivo Anti inflamatório Site www.gilbertodenucci.com History of inflammation and NSAIDs For 3,500 years inflammation has been treated with preparations originating from plants containing salicylates. • myrtle leaves (Myrtus) • willow bark (Salix) • poplar bark (Populus) • meadowsweet (Spiraea) • wintergreen oil (Gaultheria) Aspirin On 6th March 1899, ‘ Aspirin ’ was registered as a trademark with the Imperial Patent Office in Berlin. WORLDWIDE Production - 36,000 tons / year Use - 70 tablets / person / year acetyl ‘A’ Spiraea ‘SPIRIN’ Cyclo-oxygenase Hypothesis - 1970’s membrane phospholipids (-) Phospholipase A2 glucocorticoids arachidonic acid Classical (-) NSAIDs COX Stomach Kidney Endothelium Platelets PGE2/PGI2 PGE2/PGI2 PGI2 TXA2 gastric cytoprotection renal blood flow haemostasis Physiological Effects Inflammatory Sites PGE2 inflammatory mediators Inflammation Roles of Prostaglandins in the 1970’s • • • • • • Pyretic (Feldberg & Gupta, 1973; Milton & Wendlandt, 1973) Pro-inflammatory (Willis, 1969) Hyperalgesic (Ferreira, 1972) Inhibit gastric acid secretion (Whittle, 1976) Contract the uterus (Bergstrom et al .,1968) Increase renal blood flow (Lonigro et al., 1973) Cyclooxygenase inhibitors: From pharmacology to clinical read-outs Biochimica et Biophysica Acta 1851 (2015) 422–432 – Fig 04 Long-term effects of low-dose aspirin (0.45 mg/kg per day) on platelet TXB2 and renal PGI2 synthesis. Roles of Prostaglandins in the 1970’s beneficial NSAID effects • • • • • • Pyretic (Feldberg & Gupta, 1973; Milton & Wendlandt, 1973) Pro-inflammatory (Willis, 1969) Hyperalgesic (Ferreira, 1972) Inhibit gastric acid secretion (Whittle, 1976) Contract the uterus (Bergstrom et al .,1968) Increase renal blood flow (Lonigro et al., 1973) harmful NSAID effects Increasing COX-2 selectivity* Comparative upper GI toxicity and COX-2 selectivity naproxen 10 9 8 7 6 5 4 3 2 1 0 nabumetone / 6MNA flurbiprofen tolmetin aspirin indomethacin ketoprofen ibuprofen diclofenac sulindac r2 0.71; p < 0.03 etodolac 1 *WHRI blood/A549 assay 2 3 4 5 6 7 8 9 Increasing upper GI toxicity 10 11 Cyclo-oxygenase Hypothesis - 1990’s membrane phospholipids (-) Phospholipase A2 glucocorticoids (-) arachidonic acid COX-1 constitutive (-) Classical NSAIDS COX-2 (-) inducible Stomach Kidney Endothelium Platelets PGE2/PGI2 PGE2/PGI2 PGI2 TXA2 gastric cytoprotection renal blood flow haemostasis Physiological Effects INDUCTION: mitogens endotoxins cytokines (-) selective COX-2 inhibitors Inflammatory Sites PGE2 inflammatory mediators Inflammation Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors. The amino acid residues Val434, Arg513, and Val532 form a side pocket in COX-2 that is absent in COX-1. Nonselective inhibitors have access to the binding channels of both isoforms. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors. The amino acid residues Val434, Arg513, and Val523 form a side pocket in COX-2 that is absent in COX-1. The more voluminous residues in COX-1, Ile434, His513, and Ile532, obstruct access of the bulky side chains of COX-2 inhibitors. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation Distribution of COX-2 Present under ‘basal’ conditions: CNS (cortex, hippocampus and amygdala), stomach (small amount in superficial mucosa), kidney. After treatment with hormones or other regulatory factors: Ovaries, kidney (macula densa). After treatment with LPS, cytokines etc.: Monocytes, macrophages, endothelial cells, synoviocytes, chondrocytes, osteoblasts, amnion, CNS, pulmonary epithelial cells, smooth muscle cells. Regulation of COX-2 Expression The COX-2 promoter contains binding sites for NFkB, glucocorticoids, IL-6 and other cytokines. COX-2 is upregulated by LPS, IL-1, TNF, EGF, PDGF, TPA and serum. Induction has been seen in macrophages, endothelial cells, fibroblasts, amnion cells, glomerular mesangial cells and osteoclasts. COX-2 down-regulated by glucocorticoids, cycloheximide and anti-sense agents. Inflammatory Role for COX-1 ? In rat peritoneal and alveolar macrophages COX-1 contributes to PG synthesis in basal and stimulated states. (Wilborn et al., 1995) Positive feedback between PGE2 and COX-2: PGs generated from endogenous COX-1 may be involved in the initial induction of COX-2. (Mertz et al., 1994) Overall increase of COX-1 levels in rheumatoid synovial tissue is likely due to markedly increased cellularity. (Crofford, 1996) Physiological Role for COX-2 ? Levels of COX-2 mRNA (similar to COX-1mRNA) High - prostate, lung Medium - stomach, small intestine, uterus and mammary gland Low - kidney, liver, pancreas, testis, thymus, brain (O’Neill & Ford-Hutchinson, 1994) STOMACH Under basal conditions COX-2 is present in the surface mucous cells of the fundic and pyloric regions of the stomach. (Iseki et al., 1995) COX enzyme effects COX-2 Inhibitors and Cardiovascular Risk - VOL 336 SCIENCE - Fig 01 Cyclooxygenase inhibitors: From pharmacology to clinical read-outs Biochimica et Biophysica Acta 1851 (2015) 422–432 – Fig 01 Chemical structures of NSAIDs Cumulative Incidence of the Primary End Point of a Confirmed Upper Gastrointestinal Event among All Randomized Patients. COMPARISON OF UPPER GASTROINTESTINAL TOXICITY OF ROFECOXIB AND NAPROXEN IN PATIENTS WITH RHEUMATOID ARTHRITIS - The New England Journal of Medicine – fig 01 Kaplan–Meier Estimates of the Cumulative Incidence of Confirmed Serious Thrombotic Events. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial - n engl j med 352;11 – march 17,2005 Kaplan–Meier Estimates of the Cumulative Incidence of Investigator- Reported Congestive Heart Failure (CHF), Pulmonary Edema (PE), or Cardiac Failure (CF). Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial - n engl j med 352;11 – march 17,2005 Disposition of patients N = 3987 Celecoxib 400mg BID N = 1779 Completed Study N = 2208 Withdrawn Lost to follow-up: 0 Preexisting violation: 27 Protocol noncompliance: 585 Treatment failure:691 Adverse event:905 N = 8059 Patients Randomized N = 7968 Patients Taking Study Medication N = 1996 Diclofenac 75mg BID N = 939 Completed Study N = 1057 Withdrawn Lost to follow-up: 0 Preexisting violation: 11 Protocol noncompliance: 197 Treatment failure: 309 Adverse event: 540 N = 1985 Ibubrofen 800mg TID N = 691 Completed Study N = 1294 Withdrawn Lost to follow-up: 0 Preexisting violation: 12 Protocol noncompliance: 365 Treatment failure: 456 Adverse event: 461 N = 3409 Patients Completing Study Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Kaplan-Meier analyses of time to thromboembolic events in patients not taking aspirin from the CLASS trial. A, celecoxib versus the combined nonsteroidal antiflammatory agents (NSAIDs) ibuprofen and diclofenac combined (p 0.973 celecoxib vs NSAIDs). Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Kaplan-Meier analyses of time to thromboembolic events in patients not taking aspirin from the CLASS trial. B, celecoxib versus the individual NSAIDs (p 0.379 and 0.236, celecoxib vs diclofenac and vs ibuprofen, respectively). Comparison of Thromboembolic Events in Patients Treated With Celecoxib, a Cyclooxygenase-2 Specific Inhibitor, Versus Ibuprofen or Diclofenac - The American Journal of Cardiology Vol. 89 February 15, 2002 Duration of use of tNSAIDs and individual tNSAIDs among current users (use within a month) and risk of myocardial infarction. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities - The Journal of Clinical Investigation Comparison of major gastrointestinal events between COX-2 inhibitors and NSAID plus PPI and subgroup analysis stratified by the risk for NSAID- related GI complications Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis - J Gastroenterol (2013) 48:830–838 – Fig 03 Comparison of major gastrointestinal events between COX-2 inhibitors and NSAID plus PPI and subgroup analysis stratified by the risk for NSAID- related GI complications Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis - J Gastroenterol (2013) 48:830–838 – Fig 03 Flow of selection and censoring of ankylosing spondy- litis (AS)/spondyloarthritis (SpA) patients prior to and during the study period (January 1, 2006 through December 31, 2009). Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – fig 01 Patient demographics, medications, and comorbidities at baseline (n 5 21,872) Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 01 Events, number of patient-years (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the outcomes of interest for etoricoxib, nonselective NSAIDs, celecoxib, and those totally unexposed to any NSAID for ankylosing spondylitis/ spondyloarthritis patients Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 02 Events, number of patientyears (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the outcomes of interest for etoricoxib, nonselective NSAIDs, celecoxib, and those totally unexposed to any NSAID for ankylosing spondylitis/ spondyloarthritis patients (cont’d) Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 02 vents, number of patient-years (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the outcomes of interest for etoricoxib, nonselective NSAIDs, celecoxib, and those totally unexposed to any NSAID for AS patients Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 03 Events, number of patient-years (PYs) at risk, and unadjusted and adjusted incidence rates (IRs) for the outcomes of interest for etoricoxib, nonselective NSAIDs, celecoxib, and those totally unexposed to any NSAID for other SpA patients Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 04 Events, number of patient-years (PYs) at risk, unadjusted incidence rates (IRs), and adjusted relative risks (RRs) for the outcomes of interest for the subgroups of most used nonselective NSAIDs (diclofenac, ketoprofen, naproxen, ibuprofen, and indomethacin) and patients not exposed to any NSAID for AS/SpA patients Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 05 Events, number of patient-years (PYs) at risk, unadjusted incidence rates (IRs), and adjusted relative risks (RRs) for the outcomes of interest for the subgroups of most used nonselective NSAIDs (diclofenac, ketoprofen, naproxen, ibuprofen, and indomethacin) and patients not exposed to any NSAID for AS/SpA patients (cont’d) Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study Arthritis Care & Research - Vol. 67, No. 8, August 2015, pp 1137–1149 – Tab 05 the risks for adverse outcome events related to nonselective NSAIDs, etoricoxib, and celecoxib exposure in AS and SpA patients in Sweden are not statistically different. No significantly increased risks were identified in this In conclusion, the results of this study suggest that in regular care, population of AS and SpA patients for etoricoxib compared to nonselective NSAIDs and celecoxib. Unexposed patients had considerably more baseline comorbidities and a higher RR for atherosclerotic events and congestive heart failure, suggesting that confounding by indication significantly affects the observed AE rates associated with NSAIDs in clinical practice. The lessons from the “COX-2 debacle” will likely continue to increase in number and be reevaluated for years to come. Looking at the above information though, we can at least conclude that: 1) NSAIDs, whether c2sNSAID or nsNSAID, have detrimental CV effects that become more apparent the longer they are given. Hence, the lowest dose, least frequent dosing, and shortest duration use are always advised (similar to opioids); 2) The severity of these CV effects relates more to the individual agent than the COX-2 selectivity of the drug; 3) The mechanisms of such CV effects are not fully known but is not the result of a prothrombotic state, and so this theory should be disre- garded in future reviews; The lessons from the “COX-2 debacle” will likely continue to increase in number and be reevaluated for years to come. Looking at the above information though, we can at least conclude that: 4) The currently proven GI ben- efits of c2sNSAIDs are no different than a combination of PPI/nsNSAID, assuming patient compliance with the PPI, but there may be benefit in highly atrisk patients needing to use a combination PPI/c2sNSAID; 5) The lack of plate- let inhibition by c2SNSAIDs remains a clear factor in their use in the perioperative period over nsNSAIDs.