Pharmacology, Pharmaceutics and Clinical Use of Aspirin: A Narrative Review
Background: Aspirin is one of the most frequently used and cheapest drugs in medicine. Since its first synthesis in 1897, several medicinal roles and mechanisms of action of Aspirin have become apparent, the latest among these being its role in cancer prevention and treatment.
Objective: We present a review of Aspirin's biochemistry and pharmacology, as well as the clinical use of Aspirin. The communiqué also suggests possible strategies for maximizing the gain of Aspirin as a wonder-drug of the future.
Methods: The literature search strategy covered printed and online sources, including manual library search (PubMed), Embase, Medline, and Cochrane Library. For papers written in English and published in the last ten years. A systematic analysis of available data was subsequently performed based on the review questions. An estimated 155 articles were found online, and twenty-eight articles utilized in the final analysis.
Discussion: Aspirin belongs to the non-steroidal anti-inflammatory drugs with a wide range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. Discovery of antiplatelet effects led to the increasing use of Aspirin as an anti-thrombotic agent in the prevention of cardiovascular diseases from the 1980s, and firm evidence supporting its usefulness has continued to accumulate. Aspirin irreversibly inhibits platelet function by acetylating cyclooxygenase (COX), which is involved in the production of a potent platelet stimulator, thromboxane A2. The inhibition of COX-2 by Aspirin forms the basis of its anticipated role in preventing colorectal cancer and Alzheimer's disease and the inhibition of the progression of these diseases. It has been pointed out that the incidence of cardiovascular events tends to be high among patients who are Aspirin resistant, but the reason for this increased incidence remains unclear.
Conclusion: The emerging future interest is to accrue evidence in favor of Aspirin as the novel therapeutic drug for combating severe acute inflammation and thrombosis associated with the cytokine storm in COVID-19 patients. Notably, a randomized clinical trial, to test a range of potential treatments for COVID-19, includes low-dose Aspirin as anti-inflammatory and antiplatelet treatment.
Keywords: Aspirin; Anti-platelet; Nonsteroidal Anti-inflammatory Drug; Pharmaceutic; Pharmacodynamic; Pharmacokinetic.
2. Mahdi JG, Mahdi AJ, Bowen ID. The historical analysis of aspirin discovery, its relation to the willow tree and anti-proliferative and anticancer potential. Cell Prolif. 2006; 39:147–155.
3. Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000;321:1591–1594
4. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003; 110: 255–258.
5. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971; 231:232–235.
6. Miner J, Hoffhines A. The discovery of aspirin's antithrombotic effects. Tex Heart Inst J. 2007; 34:179–186.
7. Cuzick J, Otto F, Baron JA, et al. Aspirin and non-steroidal antiinflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009; 10:501–507.
8. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med. 2005; 353:2373–2383.
9. Patil KR, Mahajan UB, Unger BS, Goyal SN, Belemkar S, Surana SJ et al. Animal Models of Inflammation for Screening of Anti-inflammatory Drugs: Implications for the Discovery and Development of Phytopharmaceuticals. MDPI-International Journal Molecular Sciences 2019; 20 (4367): 1-38. doi:10.3390/ijms20184367
10. Calixto JB, Otuki MF, Santos ARS. Anti-Inflammatory Compounds of Plant Origin. Part I. Action on Arachidonic Acid Pathway, Nitric Oxide and Nuclear Factor κ B (NF-κB). Planta Med. 2003; 69: 973–983.
11. Chung HJ, Lee HS, Shin JS, Lee SH, Park BM, Youn YS et al. Modulation of acute and chronic inflammatory processes by a traditional medicine preparation GCSB-5 both in vitro and in vivo animal models. J. Ethnopharmacol. 2010; 130: 450–459.
12. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: How hot is the link? Biochem. Pharmacol. 2006; 72: 1605–1621.
13. Divya T, Latha P, Usha K, Anuja G, Suja S, Shyamal S. Anti-inflammatory, analgesic and anti-lipid peroxidative properties of Wattakaka volubilis (Linn. f.) Stapf. Indian J. Nat. Prod. Resour. 2009; 8: 137–141.
14. Jo WS, Yang KM, Choi YJ, Jeong CH, Ahn KJ, Nam BH et al. In vitro and in vivo anti-inflammatory effects of pegmatite. Mol. Cell. Toxicol. 2010; 6: 195–202.
15. Ornelas A, Zacharias-Millward N, Menter DG, Davis JS, Lichtenberger L, Hawke D et al. Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev 2017; 36:289–303 DOI 10.1007/s10555-017-9675-z
16. Fersht AR, Kirby AJ. Hydrolysis of aspirin. Intramolecular general base catalysis of ester hydrolysis. Journal of the American Chemical Society 1967; 89(19): 4857–4863.
17. St. Pierre T, Jencks WP. Intramolecular catalysis in the reactions of nucleophilic reagents with aspirin. Journal of the American Chemical Society 1968; 90(14), 3817–3827
18. Choudhary A, Kamer KJ, Raines RT. An n→π* interaction in aspirin: Implications for structure and reactivity. The Journal of Organic Chemistry 2011; 76(19): 7933–7937.
19. Chandrasekhar S, Kumar HV. The reaction of aspirin with base. Tetrahedron Letters 2011; 52: 3561–3564.
20. Dakin HD, West RJ. A general reaction of amino acids. The Journal of Biological Chemistry 1928; 78: 91–104.
21. Hendrix BM, Paquin F. The effect of alkali treatment upon acetyl proteins. The Journal of Biological Chemistry 1938; 124: 135–145.
22. Bundgaard H, Larsen C. Intramolecular and intermolecular transformations of aspirin in nonhydroxylic solvents. Journal of Pharmaceutical Sciences 1976; 65(5): 776–778.
23. Pinckard RN, Hawkins D, Farr RS. In vitro acetylation of plasma proteins, enzyme and DNA by aspirin. Nature 1968; 219: 68–69.
24. Al-Mondhiri H, Marcus A, Spaet TH. Acetylation of human platelets by aspirin. Federation Proceedings 1969; 28: 576.
25. Passacquale G, Phinikarudou A, Warboys C, Cooper M, Lavin B, Alfieri A et al. Aspirin induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration. British Journal of Pharmacology 2015; 172(14): 3548–3564.
26. Watala C, Gwozdzinski K. Effect of aspirin on conformation and dynamics of membrane proteins in platelets and erythrocytes. Biochemical Pharmacology 1993; 45: 1343–1349.
27. Gerig JT, Katz KE, Reinheimer JD, Sullivan GR et al. Examination of the aspirin acetylation site of human serum albumin by 13C NMR spectroscopy. Organizational Magnetic Resonance 1981; 15: 158–161.
28. Pandita S, Zakir SG. An efficient microscale procedure for the synthesis of aspirin. Journal of Chemical Education 1998; 75(6): 770.
29. Needs CJ, Brooks PM. Clinical pharmacokinetics of the salicylates. Clinical Pharmacokinetics 1985; 10(2): 164–177
30. Xu ASL, Macdonald JM, Labotka RJ, London RE. NMR study of the sites of human hemoglobin acetylated by aspirin. Biochemica et Biophysica Acta 1999; 1432: 333–349.
31. Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nature Structural Biology 1995; 2: 637–643.
32. Lucido MJ, Orlando BJ, Vecchio AJ, Malkowski MG. Crystal structure of aspirin-acetylated human cyclooxygenase-2: insight into the formation of products with reversed stereochemistry. Biochemistry 2016; 55(8):1226–1238.
33. Pinckard RN, Hawkins D, Farr RS. The inhibitory effect of salicylate on the acetylation of human albumin by acetylsalicylic acid. Arthritis and Rheumatism 1970; 13(4): 361–368.
34. Alfonso LF, Srivenugopal KS, Arumuga TV, Abbruscato TJ, Weidanz JA, Bhat GJ. Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells. International Journal of Oncology 2009; 34: 597–608.
35. Yin MJ, Yamamoto Y, Gaynor RB. The antiinflammatory agents-aspirin and salicylate inhibit the activity of IKB kinase-B. Nature 1998; 396(6706): 77–80.
36. McCarty MF, Block KI. Preadministration of high dose salicylates, suppressors of NF-KB activation may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy. Integrative Cancer Therapies 2006; 5(3): 252–268.
37. Rowland M, Riegelman S, Harris PA, Sholkoff SD. Absorption kinetics of aspirin in man following oral administration of an aqueous solution. Journal of Pharmaceutical Sciences 1972; 61(3): 379–385.
38. Rainsford KD, Ford NL, Brooks PM, Watson HM. Plasma aspirin esterases in normal individuals, patients with alcoholic liver disease and rheumatoid arthritis: characterization and importance of the enzymic components. European Journal of Clinical Investigation 1980; 10(5): 413–420.
39. Zhou G, Marathe GK, Willard B, McIntyre TM. Intracellular erythrocyte platelet-activating factor acetylhydrolase I inactivates aspirin in blood. The Journal of Biological Chemistry 2011; 286(40): 34820–34829.
40. Day RO, Graham GG, Williams KM. Pharmacokinetics of non-steroidal anti-inflammatory drugs. Baillière's Clinical Rheumatology 1988; 2(2): 363-393. https://doi.org/10.1016/S0950-3579(88)80019-0
41. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. Acetylation of a particulate fraction. Journal of Clinical Investment 1975; 56(3): 624–632.
42. Rowland M, Riegelman S. Pharmacokinetics of acetylsalicylic acid and salicylic acid after intravenous administration in man. Journal of Pharmaceutical Sciences 1968; 57: 1313–1319.
43. Bhatt D, Grosser T, Dong JF, Logan D, Jeske W, Angiolillo DJ et al. Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus. JACC 2017; 69(6): 604–611.
44. Lichtenberger LM, Phan T, Fang D, Edler S, Philip J, LiGeng T et al. Bioavailability of aspirin in rats comparing the drug uptake into gastrointestinal tissue and vascular and lymphatic systems: implications on aspirin’s chempreventive action. Journal of Physics and Pharmacology 2016; 67(5): 635–642.
45. Verbeeck RK, Cardinal JA. Plasma protein binding of salicylic acid, phenytoin, chlorpromazine, and pethidine using equilibrium dialysis and ultracentrifugation. Arzneimittel Forschung 1985; 35: 903–906.
46. Aarons L, Clifton P, Fleming G, Rowland M. Aspirin binding and the effect of albumin on spontaneous and enzyme catalyzed hydrolysis. The Journal of Pharmacy and Pharmacology 1980; 32: 537–543.
47. Rendell M, Nierenberg J, Brannan C, Valentine JL, Stephen PM, Dodds S et al. Inhibition of glycation of albumin and hemoglobin by acetylation in vitro and in vivo. Journal of Laboratory and Clinical Medicines 1968; 108: 286–293.
48. Hawkins D, Pinckard RN, Crawford IP, Farr RS. Structural changes in human serum albumin induced by ingestion of acetylsalicylic acid. The Journal of Clinical Investigation 1969; 48(3): 536–542.
49. Ashton JM, Bolme P, Zerihun B. Protein binding of salicylic acid and salicyluric acid in serum from malnourished children: the influence of albumin competitive binding and non-esterified fatty acids. Journal Pharmacy and Pharmacology 1989; 41: 474–480.
50. Moran CJ, Walker WHC. The binding of salicylate to human serum. Biochemical Pharmacology 1968; 17: 153–156.
51. Zarolinski JF, Keresztes NS, Mais RF, Oester YT. Effect of temperature on the binding of salicylate by human serum albumin. Biochemical Pharmacology 1974; 23: 1767–1776.
52. Kuehl GE, Bigler J, Potter JD, Lampe JW. Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes 2006; 34(2): 199-202
53. Alegbeleye BJ, Akpoveso OP, Alegbeleye AJ, Mohammed RK, Esteban-Zubero E. The Novel Aspirin as Breakthrough Drug for COVID-19: A Narrative Review. Iberoamerican Journal of Medicine 00 (2020) XXX–XXX. http://doi.org/10.5281/zenodo.3970519
54. Elwood P, Stillings M. New uses for old drugs: Aspirin — the first miracle drug. The Pharmaceutical Journal10 MAR 2001 https://www.pharmaceutical-journal.com/learning/learning-article/new-uses-for-old-drugs-aspirin-the-first-miracle-drug/20004121.article?firstPass=false
55. Pierpoint WS. The natural history of salicylic acid, plant product and mammalian medicine. Interdisciplinary Sci Rev 1997; 22:45-52.
56. Stone E. An account of the success of the bark of the willow in the cure of agues. Philos Trans 1763; 53:195-200.
57. Wilthauer J, Wohlgemut J. Uber aspirine (acetylsalicylsaure). Ther Mh (Halbmh) 1899; 13:276.
58. Chiang N, Serhan CN. Aspirin Triggers Formation of Anti-inflammatory Mediators: New Mechanism for an Old Drug. Discovery Medicine- Published on July 14, 2009. (Accessed online June 20, 2020). www.discoverymedicine.com/Nan-Chiang/2009/07/14/aspirin-triggers-formation-of-anti-inflammatory-mediators-new-mechanism-for-an-old-drug
59. Needleman P, Isakson PC. The discovery and function of COX-2. Journal of Rheumatology (Supplement) 1997; 49:6-8
60. Serhan CN, Chiang N. Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: entree for resoleomics. Rheumatic Disease Clinics of North America 2004; 30:69-95
61. Kasotakis G, Pipinos I.I, Lynch TG. Current evidence and clinical implications of aspirin resistance. Journal of Vascular Surgery 2009; 50:1500-1510. doi:10.1016/j.jvs.2009.06.023
62. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:938-949.
63. Palabrica T, Lobb R, Furie BC et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 1992; 359:848-851
64. Roth GJ, Calverley DC. Aspirin, platelets, and thrombosis: theory and practice. Blood 1994; 83:885-898
65. Espinosa EVP, Murad JP, Khasawneh FT. Aspirin: Pharmacology and Clinical Applications. Thrombosis Volume 2012, Article ID 173124, 15 pages. doi:10.1155/2012/173124
66. Altman R, Carreras L, Diaz R et al. Collaborative overview of randomized trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. British Medical Journal 1994; 308 (6921): 81–106
67. Gross PL, Weitz JI. New antithrombotic drugs. Clinical Pharmacology and Therapeutics, 2009; 86 (2): 139–146
68. Gaussem P, Reny JL, Thalamas C, Chatelain N, Kroumova M, Jude B et al. The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies. Journal of Thrombosis and Haemostasis 2005; 3 (7):1437–1445
69. Dai Y, Ge J. Clinical Use of Aspirin in Treatment and Prevention of Cardiovascular Disease. Thrombosis Volume 2012, Article ID 245037, 7 pages. doi:10.1155/2012/245037
70. Baigent C, Sudlow C, Collins R, Peto R. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. British Medical Journal 2002; 324 (7329): 71–86
71. Antithrombotic Trialists’ (ATT) Collaboration, “Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials.” The Lancet 2009; 373 (9678):1849–1860
72. Theroux P, Ouimet H, McCans J et al. Aspirin, heparin, or ´ both to treat acute unstable angina. New England Journal of Medicine 1988; 319 (17); 1105–1111
73. Wallentin LC, Berglund U, Nyman I et al. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, complicating coronary angioplasty. Circulation 1987; 76(1):125–134
74. Anderson JL, Adams CD, Antman EM et al. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Journal of the American College of Cardiology 2007; 50(7): e1–e157
75. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation 2004; 110 ( 5): 588– 636
76. Hartney TJ, Shapiro S, Jain KM et al. The physicians’ health study: aspirin for the primary prevention of myocardial infarction. New England Journal of Medicine 1988; 318 (14): 924–926
77. Jull-Moller S, Edvardsson N, Jahnmatz B, Rosen A, Sorensen S, Omblus R. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. The Lancet 1992; 340 (8833):1421–1425
78. Gibbons RJ, Abrams J, Chatterjee K et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003; 107(1):149–158
79. Goldman S, Copeland J, Mortiz T et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988; 77(6): 1324–1332
80. Gluckman TJ, McLean RC, Schulman SP et al. Effects of aspirin responsiveness and platelet reactivity on early vein graft thrombosis after coronary artery bypass graft surgery. Journal of the American College of Cardiology 2011;57(9):1069–1077
81. Kubota N, Kasai T, Miyauchi K, Njaman W, Kajimoto K, Akimoto Y. Therapy with statins and aspirin enhances long-term outcome of percutaneous coronary intervention. Heart and Vessels 2008; 23(1):35–39
82. Njaman W, Miyauchi K, Kasai T et al. Impact of aspirin treatment on long-term outcome (over 10 years) after percutaneous coronary intervention,” International Heart Journal 2006; 47 (1): 37–45
83. Fox KAA, Mehta SR, Peters R et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non- ST-elevation acute coronary syndrome: the clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial. Circulation 2004; 110 (10):1202–1208
84. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery: a placebo-controlled, randomized study. Circulation 1991; 83(5): 1526–1533
85. Ferraris VA, Ferraris SP, Moliterno DJ et al. The society of thoracic surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary). Annals of Thoracic Surgery 2005; 79(4): 1454–1461
86. Taylor RR, Gibbons FA, Cope GD, Cumpston GN, Mews GC, Luke P. Effects of low-dose aspirin on restenosis after coronary angioplasty. American Journal of Cardiology 1991;68(9):874–878
87. Lembo NJ, Black AJR, Roubin GS et al. Effect of pretreatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty. American Journal of Cardiology 1990; 65(7): 422–426
88. Barnathan ES, Schwartz JS, Taylor L. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987; 76(1): 125–134
89. Eagle KA, Guyton RA, Davidoff R et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation 2004; 110(14): e340–e437
90. Smith Jr. SC, Feldman TE, Hirshfeld JW Jr. et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113(7): e166–e286
91. Medi C, Hankey GJ, Freedman SB. Stroke risk and antithrombotic strategies in atrial fibrillation. Stroke 2010; 41 (11): 2705–2713
92. Kalra L, Lip GYH. Antithrombotic treatment in atrial fibrillation. Heart 2007;93 (1): 39–44
93. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3):4295–4565
94. Dehaene I. European atrial fibrillation trial. Acta Neurologica Belgica 1988; 88 (3): 172–173
95. Peto R, Gray R, Collins R et al. Randomized trial of prophylactic daily aspirin in British male doctors. British Medical Journal 1988; 296(6618): 313–316
96. Meade TW, Wilkes HC, Kelleher CC et al. Thrombosis prevention trial: randomized trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease in men at increased risk. The Lancet 1998; 351(9098):233–241
97. Parving HH. Hypertension Optimal Treatment (HOT) trial. The Lancet 1998; 352 (9127): 574–575
98. Roncaglioni MC. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomized trial in general practice. Lancet 2001; 357(9250): 89–95
99. Ridker PM, Cook NR, Lee IM et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine 2005; 352(13): 1293–1304
100. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. Journal of the American Medical Association 2006; 295(3): 306–316
101. Helgason CM, Bolin KM, Hoff JA, Winkler SR, Mangat A, Tortorice KL, Brace LD. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25:2331-2336
102. Weng Z, Li X, Li Y, Lin J, Peng F, Niu W. The association of four common polymorphisms from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity: a meta-analysis. PLoS One 2013; 8(11):e78093.
103. Du G, Lin Q, Wang J. A brief review on the mechanisms of aspirin resistance. International journal of cardiology 2016; 220: 21-26.
104. CLASP: a randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) Collaborative Group. Lancet 1994; 343:619-629.
105. Richards M, Meade TW, Peart S, Brennan PJ, Mann AH. Is there any evidence for a protective effect of anti-thrombotic medication on cognitive function in men at risk of cardiovascular disease? Some preliminary findings. BMJ 1997; 62:269-272.
106. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiological studies. Neurology 1996; 47:425-432.
107. Stewart WF, Kawas C, Corrada M, Metter EJ. Risk of Alzheimer’s disease and duration of NSAID use. Neurology 1997; 48:626-632.
108. Christen WG, Manson JE, Glynn RJ, Ajani UA, Schaumberg DA, Sperduto RD et al. Lowdose aspirin and risk of cataract and subtypes in a randomized trial of US physicians. Ophthal Epidem 1998; 5:133-142.
109. Morgan G. Aspirin and cancer. Cardiff: University of Wales College of Medicine; 1998.
110. Morgan G. Beneficial effects of NSAIDs in the gastrointestinal tract. Eur J Gastrol Hepatol 1999; 11:393-400.
111. Matsui T, Abe K, Honda T, Yasukawa K, Takanashi JI and Hamada H Aspirin Dose and Treatment Outcomes in Kawasaki Disease: A Historical Control Study in Japan. Front. Pediatr. 2020; 8: 249. doi: 10.3389/fped.2020.00249
112. Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers toes in children (in Japanese). Arerugi. 1967; 16:178–222.
113. Gordon JB, Kahn AM, Burns JC. When children with Kawasaki disease grow up: myocardial complications in adulthood. J Am Coll Cardiol. 2009; 54:1911–1920. doi: 10.1016/j.jacc.2009.04.10
114. Newburger JW, Takahashi M, Burns JC. Kawasaki disease. J Am Coll Cardiol. 2016; 67: 1738–1749. doi: 10.1016/j.jacc.2015.12.073
115. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF, Gewitz M et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American heart association. Circulation 2017; 135:e927–99. doi: 10.1161/CIR.0000000000000484
116. Research committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery: Committee for development of guidelines for medical treatment of acute Kawasaki disease. Guidelines for medical treatment of acute Kawasaki disease: report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (2012 revised version). Pediatr Int. 2014; 56:135–158. doi: 10.1111/ped.12317
117. Aspirin information from Drugs.com. Drugs.com. Archived from the original on 9 May 2008. Retrieved 20 August 2020.
118. Oral Aspirin information. First DataBank. Archived from the original on 18 September 2000. Retrieved 20 August 2020.
119. Raithel M, Baenkler HW, Naegel A, Buchwald F, Schultis HW, Backhaus B et al. Significance of salicylate intolerance in diseases of the lower gastrointestinal tract (PDF). Journal of Physiology and Pharmacology 2005; 56(Suppl 5): 89–102. PMID 16247191. Archived (PDF) from the original on 9 April 2011.
120. Senna GE, Andri G, Dama AR, Mezzelani P, Andri L. Tolerability of imidazole salicylate in aspirin-sensitive patients. Allergy Proceedings 1995; 16 (5): 251–254. doi:10.2500/108854195778702675. PMID 8566739.
121. PDR guide to over the counter (OTC) drugs. Archived from the original on 10 April 2008. Retrieved 20 August 2020.
122. Livingstone FB. Frequencies of hemoglobin variants: thalassemia, the glucose-6-phosphate dehydrogenase deficiency, G6PD variants, and ovalocytosis in human populations. Oxford University Press. ISBN 978-0-19-503634-3. (1985).
123. Dengue and dengue hemorrhagic fever: information for health care practitioners. Archived from the original on 17 March 2008. Retrieved 19 June2020.
124. Macdonald S. Aspirin use to be banned in under 16 year olds. BMJ 2002; 325 (7371):988c doi:10.1136/bmj.325.7371.988/c.
125. Sørensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. The American Journal of Gastroenterology 2000; 95 (9): 2218–2224. PMID 11007221.
126. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ.2007; 177(4): 347–51. doi:10.1503/cmaj.070186.
127. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? Physiological Reviews 2008; 88 (4): 1547–65. doi: 10.1152/physrev.00004.2008. PMID 18923189.
128. Fiorucci S, Santucci L, Wallace JL, Sardina M, Romano M, del Soldato P et al. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa. Proceedings of the National Academy of Sciences of the United States of America 2003; 100 (19): 10937–10941.
129. General chemistry online: FAQ: Acids and bases: What is the buffer system in buffered aspirin? Antoine.frostburg.edu. Archived from the original on 14 April 2011. Retrieved 11 August 2020.
130. Dammann HG, Saleki M, Torz M, Schulz HU, Krupp S, Schürer M, et al. Effects of buffered and plain acetylsalicylic acid formulations with and without ascorbic acid on gastric mucosa in healthy subjects. Alimentary Pharmacology & Therapeutics 2004; 19 (3): 367–374.
131. Konturek PC, Kania J, Hahn EG, Konturek JW. Ascorbic acid attenuates aspirin-induced gastric damage: role of inducible nitric oxide synthase. Journal of Physiology and Pharmacology 2006; 57 Suppl 5 (5): 125–136.
132. Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL. Salicylate induces tinnitus through activation of cochlear NMDA receptors. The Journal of Neuroscience 2003; 23 (9): 3944–3952.
133. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. The New England Journal of Medicine1999; 340 (18): 1377–1382.
134. Reye's syndrome. NHS Choices. National Health Service. 12 January 2016. Retrieved 10 August 2016.
135. Are You Sensitive to Aspirin? Here is Some Reasons Why. Health Essentials from Cleveland Clinic. 5 February 2015. Retrieved 5 August 2020.
136. Stadelmann WK, Digenis AG, Tobin GR. Impediments to wound healing. American Journal of Surgery 1998; 176 (2A Suppl): 39S–47S. doi:10.1016/S0002-9610(98)00184-6.
137. Maessen-Visch MB, de Roos KP. Dutch Venous Ulcer guideline update. Phlebology 2014; 29 (1 suppl): 153–156.
138. Berges-Gimeno MP, Stevenson DD. Nonsteroidal anti-inflammatory drug-induced reactions and desensitization. The Journal of Asthma 2004; 41 (4): 375–384.
139. Vernooij MW, Haag MD, van der Lugt A, Hofman A, Krestin GP, Stricker BH et al. (June 2009). Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study. Archives of Neurology 66 (6): 714–720.
140. Gorelick PB. Cerebral microbleeds: evidence of heightened risk associated with aspirin use. Archives of Neurology 2009; 66 (6): 691–693. doi:10.1001/archneurol.2009.85.
141. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998; 280 (22): 1930–1935.
142. Saloheimo P, Ahonen M, Juvela S, Pyhtinen J, Savolainen ER, Hillbom M. Regular aspirin-use preceding the onset of primary intracerebral hemorrhage is an independent predictor for death. Stroke 2006; 37 (1): 129–133.
143. Medical knowledge self-assessment program for students, By American College of Physicians, Clerkship Directors in Internal Medicine, Nephrology 227, Item 29
144. Scher KS. Unplanned reoperation for bleeding. The American Surgeon 1996; 62 (1): 52–55. PMID 8540646.
145. FDA strengthens warning of heart attack and stroke risk for non-steroidal anti-inflammatory drugs. FDA. 9 July 2015. Archived from the original on 11 July 2015. Retrieved 19 June 2020.
146. Kreplick LW. Salicylate toxicity in emergency medicine. Medscape. 2001. Archived from the original on 31 August 2012.
147. Gaudreault P, Temple AR, Lovejoy FH. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics 1982; 70 (4): 566–569. PMID 7122154. (primary source)
148. Marx J. Rosen's emergency medicine: concepts and clinical practice. Mosby/Elsevier. p. 2242. (2006). ISBN 978-0-323-02845-5.
149. Morra P, Bartle WR, Walker SE, Lee SN, Bowles SK, Reeves RA. Serum concentrations of salicylic acid following topically applied salicylate derivatives. The Annals of Pharmacotherapy 1996; 30 (9): 935–940. doi:10.1177/106002809603000903.
150. Baselt R. Disposition of toxic drugs and chemicals in man (9th ed.). Seal Beach, California: Biomedical Publications. 2011. pp. 20–23. ISBN 978-0-9626523-8-7.
151. Information for Healthcare Professionals: Concomitant Use of Ibuprofen and Aspirin. FDA. U.S. Department of Health & Human Services. September 2006. Archived from the original on 19 October 2010. Retrieved 22 August 2020.
152. Katzung BG. Basic and clinical pharmacology. McGraw-Hill. 1998. p. 584. ISBN 978-0-8385-0565-6.
153. Loh HS, Watters K, Wilson CW. The effects of aspirin on the metabolic availability of ascorbic acid in human beings. Journal of Clinical Pharmacology 1973; 13 (11): 480–486. doi:10.1002/j.1552-4604.1973.tb00203.x.
154. Basu TK. Vitamin C-aspirin interactions. International Journal for Vitamin and Nutrition Research. Supplement = Internationale Zeitschrift Fur Vitamin- und Ernahrungsforschung. Supplement. 1982; 23: 83–90.
155. Ioannides C, Stone AN, Breacker PJ, Basu TK. Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs. Biochemical Pharmacology.1982; 31 (24): 4035–4038. doi:10.1016/0006-2952(82)90652-9.
156. Awtry EH, Loscalzo J. Aspirin-Cardiovascular Drugs. Circulation 2000; 101:1206-1218. http://www.circulationaha.org
157. Clarke RJ, Mayo G, Price P, Fitzgerald GA. Suppression of thromboxane A2 but not systemic prostacyclin by controlled-release aspirin. N Engl J Med. 1991; 325:1137–1141.
158. Keimowitz RM, Pulvermacher G, Mayo G, Fitzgerald DJ. Aspirin and platelets: transdermal modification of platelet function: a dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis. Circulation. 1993; 88:556–561.
159. Jaszewski R. Frequency of gastroduodenal lesions in asymptomatic patients on chronic aspirin or nonsteroidal antiinflammatory drug therapy. J Clin Gastroenterol. 1990; 12:10–13.
160. Savon JJ, Allen ML, DiMarino AJ Jr, Hermann GA, Krum RP. Gastrointestinal blood loss with low dose (325 mg) plain and enteric-coated aspirin administration. Am J Gastroenterol. 1995; 90:581–585.
161. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348:1413–1416.
162. Hawthorne AB, Mahida YR, Cole AT, Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. Br J Clin Pharmacol. 1991; 32:77–83.
163. Stampfer MJ, Jakubowski JA, Deykin D, Schafer AI, Willett WC, Hennekens CH. Effect of alternate-day regular and enteric-coated aspirin on platelet aggregation, bleeding time, and thromboxane A2 levels in bleeding-time blood. Am J Med. 1986; 81:400–404
164. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other nonsteroidal anti-inflammatory drugs. J Biol Chem. 1993; 268: 6610–6614.
165. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer non-steroidal anti-inflammatory drugs. Am J Med. 1993; 95(suppl 2A):40S–44S.
166. Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, Marnett LJ. Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science 1998; 280:1268–1270.
167. Lanza FL. Gastrointestinal toxicity of newer nonsteroidal antiinflammatory drugs. Am J Gastroenterol. 1993; 88:1318–1323.
168. Roth SH, Tindall EA, Jain AK, McMahan FG, April PA, Bockow BI, Cohen SB, Fleischmann RM. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med. 1993; 153:2565–2571.
169. Johnson SA, Leib MS, Forrester SD, Marini M. The effect of misoprostol on aspirin-induced gastroduodenal lesions in dogs. J Vet Intern Med. 1995; 9:32–38.
170. Bowersox TS, Lipowitz AJ, Hardy RM, Johnston GR, Hayden DW, Schwartz S, King VL. The use of a synthetic prostaglandin E1 analog as a gastric protectant against aspirin-induced hemorrhage in the dog. J Am Animal Hosp Assoc. 1996; 32:401–407.
171. Lanza FL, Kochman RL, Geis GS, Rack EM, Deysach LG. A double-blind, placebo-controlled, 6-day evaluation of two doses of misoprostol in gastroduodenal mucosal protection against damage from aspirin and effect on bowel habits. Am J Gastroenterol. 1991; 86:1743–1748.
172. Takeuchi K, Yasuhiro T, Asada Y, Sugawa Y. Role of nitric oxide in pathogenesis of aspirin-induced gastric mucosal damage in rats. Digestion 1998; 59:298–307.
173. Takeuchi K, Ukawa H, Konaka A, Kitamura M, Sugawa Y. Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats: comparison with plain aspirin. J Pharm Exp Ther. 1998; 286:115–121.
174. Wallace JL, McKnight W, Del Soldato P, Baydoun AR, Cirino G. Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. J Clin Invest. 1995; 96:2711–2718.
175. Ukawa H, Yamakuni H, Kato S, Takeuchi K. Effects of cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal antiinflammatory drugs on mucosal ulcerogenic and healing responses of the stomach. Digest Dis Sci. 1998; 43:2003–2011.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).