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CPY Document Aspirin1 1. Chemical and Physical Solubility Characteristics One gram dissolves in 300 ml water at 25°C, in 100 ml water at 37°C, in 5 ml ethanol, 17 ml 1.1 Narne chloroform, 10-15 ml ethyl ether; less soluble Chemical Abstracts Services Registry Number in anhydrous ether 50-78-2 Spectroscopy Chemical Abstracts Primary Name Ultraviolet, infrared, nuclear magnetic reso- Salicylic acid acetate nance and mass spectral data have been reported. IUPAC Systematic Name Stabilty Benzoic acid, 2-acetyloxy Stable in dry air but gradually hydrolyses in contact with moisture to acetic and salicylic Synonyms acids. Decomposes in boilng water. Also unsta- 2-(Acetyloxy)benzoic acid; 2-acetoxybenzoic ble in solutions of alkali hydroxides and car- acid; o-acetylsalicylic acid; acidum acetylsali- bonates (pKa 3.49 at 25°C) cylicum; acetylsalicylic acid 1.4 Technical products 1.2 Structural and rnolecular forrnulae and Trade names relative rnolecular rnass Aspirin is marketed throughout the world under many trade names, which include the foIlowing: AAS, Acentérine, Acesal, Acetard, COOH Aceticyl, Acetilum Acidulatum, Acetophen, Acetosal, Acetosalic Acid, Acetyl, Acetylin, Acetylo, Acetylsal, Actispirine, Acylpyrin, Adiro, Albyl, Albyl-Selters, Angettes, Apernyl, ~O-C-CH3 Arthrisin, Artria, A.S.A., Asadrine, Asaferm, oIl Asalite, Asatard, Aspalox, Aspegic, Aspergum, Aspinfantil, Aspirin, Aspirina, Aspirinetta, CgHa04 Relative molecular mass: 180.15 Aspirisucre, Aspisol, Aspro, Asrivo, ASS, Asteric, Astrix, Bamycor, Bamyl, Bamyl S, Bebesan, Bonakiddi, Bufferin, Calmantina, Calmo Yer 1.3 Physical and chernical properties Analgesico, Caprin, Cardiprin, Cartia, The data presented are taken from Budavari Casprium Retard, Catalgine, Cemirit, (1989) and Reynolds (1993), unless otherwise Chefarine-N, Claradin, Claragine, Codalgina specified. Retard, Colfarit, Contradol, Contrheuma, Cosprin, Delgesic, Dispril, Disprin, Dolean pH Description 8, Doleron, Dolomega, Domupirina, Dreimal, Colourless or white needle-Iike crystals or white Dulcipirina, Duramax, Easprin, ECM, Ecotrin, crystallne powder; odourless or almost odourless Empirin, Encaprin, Endydol, Enterosarin, Enterosarine, Entrophen, Extra Strength Tri- Melting-point Buffered Bufferin, Flectadol, Gepan, Globentyl, 135°C Godamed, Halgon, Helicon, Helver SaI, Idotyl, 1 AspirintI is the Bayer trade mark for acetylsalicylic acid in more than 70 countries. 43 rARC Handbooks of Cancer Prevention Istopirine, Ivépirine, Juvéprine, Kalcatyl, Kilos, When aspirn is used as an analgesic and Kynosina, Lafena, Levius, Licyl, Longasa, antipyretic, the convention al dose is 0.3-0.9 g, Magnecyl, Magnyl, Measurin, Mejoral Infantil, which may be repeated every 4-6 h according Melabon, Monobeltin 350, Neuronika, to clinical needs, up to a maximum of 4 g daily Novasen, Novid, Nu-Seals, Okal Infantil, (Reynolds & Prasad, 1982). GeneraIly, 4-8 g Orravina, Platet, Premaspin, Primaspan, daily in divided doses are used for acute mus- Primaspin, Protectin-OPT, Pyracyl, Rectosalyl, culoskeletal and joint disorders su ch as Resprin, Reumyl, Rhodine, Rhonal, Riane, SaI, rheumatoid arthritis and osteoarthritis. Salacetin, Salcetogen, Saletin, Salicilna, Use of aspirin in children has been dramati- Sanocapt, Santasal, Saspryl, Sinaspril, Solprin, cally decreased after reports of a relationship Solpyron, Solusprin, Soparine, Spalt, SRA, between its use and the development of Reye Supasa, Superaspidin, Temagin ASS, Togal ASS, syndrome, a very rare but possibly fatal combi- Trineral, Trombyl, Winsprin, Xaxa, ZORprin. nation of hepatic insufficiency and encephalo- Aspirin is also marketed in many fixed com- pathy. One of the few indications in which binations with other compounds, and especial- aspirin therapy is stil considered for children is ly with ascorbate, codeine and caffeine. juvenile rheumatoid arthritis. Suggested doses for this condition are 80 and 100 mg/kg bw 2. Occurrence, Production, Use, daily in five or six divided doses, although up Analysis and Human Exposure to 130 mg/kg daily are employed for some chil- dren. 2.1 Occurrence Aspirin is used for the secondary prevention Aspirin is not known to occur as a natural product. of myocardial infarct and stroke in patients with a history of su ch disorders. Large clinical 2.2 Production studies have shown that doses of more th an Aspirin, the acetyl derivative of salicylic acid, is 300-325 mg daily are unnecessary, and some synthesized from the acid with acetic authorities recommend doses of about anhydride using sulfuric acid as catalyst 75-100 mg daily. (Roberts & Caserio, 1965). The basis of com- mercial production, which is approximately 2.4 Analysis 40 000 t/year worldwide, was not known to the Accepted standard procedures for the assay of Working Group. aspirin are given in the national pharmacopoeias of Argentina, Australia, Brazil, China, the Czech 2.3 Use Republic, Egyt, France, Germany, Hungary, India, Aspirin and its salicylate metabolite have anal- Italy, Japan, Mexico, the Netherlands, Poland, gesic, anti-inflammatory and antipyretic prop- Portgal, Romania, the Russian Federation, Spain, erties. Aspirin was first marketed in 1899 (Vane Switzerland, Turkey, the United Kingdom and the et aL., 1990). It is used for the relief of mild-to- United States, and in the European, Nordic and moderate pain such as headache, dysmenor- international pharmacopoeias. rhoea, myalgia and dental pain. It is also used Aspirin as its metabolite salicylic acid can in acute and chronic inflammatory disorders be analysed in urine, plasma and saliva by such as rheumatoid arthritis, juvenile rheuma- colorimetry, thin-Iayer chromatography and toid arthritis and osteoarthritis. Aspirin inhibits high-performance liquid chromatography platelet aggregation and is used in the preven- (Legaz et al., 1992). ln pharmaceutical prepara- tion of arterial and venous thrombosis. tions, it can be determined by high-per- Aspirin is usuaIly taken by mouth. Various formance liquid chromatography (Menouer et dosage forms are available, including plain al., 1982) gas-liquid chromatography (Galante uncoated, buffered, dispersible, enteric-coated et al., 1981) and differential spectrophoto- and modified-release tablets. Aspirin may be metric analysis (Amer et aL., 1978) using proton administered rectaIly or intravenously as a magnetic resonance spectrometry (Vinson & complex with lycin. Kozak, 1978; AI-Badr & Ibrahim, 1981). 44 Aspirin 2.5 Hurnan exposure Table 1. Aspirin use in a California retire- Use of aspirin in the general population has ment community been estimated from studies on use of non- Aspirin use Men (5051) Women (8818) steroidal anti-inflammatory drugs (NSAlDs) No. % No. % and cancer risk with data on the consumption None 3490 69 6021 68 of aspirin by study cohorts and by community Less than daily 685 14 1417 16 control groups. Daily 876 17 1380 16 ln a study by Kune et al. (1988) in Australia, Total use 1561 31 2797 32 of 727 community controls (average age, 65 From Paganini-Hil et al. (1989) years), 67 of the 398 men (17%) and 80 of the 329 women (24%) reported using aspirin. No data were provided on the frequency or dura- per week) in each questionnaire and 15% tion of use. Paginini-Hil et al. (1989) reported reported no aspirin use in any of the periods. aspirin use in a California retirement commu- Greenberg et aL. (1993) questioned 793 nity (Table 1). The average age at the time of patients involved in a clinical trial of nutrient responding to the questionnaire was 73 years. supplements on two occasions and categorized Schreinemachers and Everson (1994) found them as using aspirin not at aIl, intermittently that 59% of 12 668 subjects (age range, 25-74 or consistently, depending on whether they years) had reported aspirin use within 30 days listed aspirin as one of their medications on of interview in the US National Health and zero, one or two questionnaires, respectively. Examination Study. The results are shown by age in Table 2. ln a study by Giovannucci et al. (1994), Aspirin use increased by 4% among men 47900 US male health professionals aged 40-75 with coronary heart disease or at high risk for years were surveyed by questionnaire. Regular coronary heart disease foIlowing publication of aspirin use was defined as more than twice the results of trials on the cardiovascular pre- weekly. A total of 33 806 (70%) did not use vention effects of aspirin. Nearly 50% of partici- aspirin (average age, 56 years) and 14 094 (30%) pants who reported a history of myocardial did (average age, 59 years). The reasons for tak- infarct, however, apparently did not take ing aspirin were surveyed in 185 men, who aspirin regularly (Shahar et aL., 1996). reported one or more of the foIlowing: cardiovas- Although the population-based data on cular disease, 25%; decrease in risk for cardiovas- aspirin use are limited, particularly with respect cular disease, 58%; joint or musculoskeletal pain, to dose, two general observations are warranted: 33%; headache, 25% and other reasons, 7.0%. · Aspirin consumption is high, in keeping Giovannucci et al. (1995a) also questioned with its ready availabilty, low cost and value in 121 701 female participants in the Nurses' a wide range of conditions. Health Study (age range, 30-55 years) on four · Because the incidence of musculoskeletal occasions over eight years; 15% reported regu- and cardiovascular disease increases with age, lar aspirin use (defined as two or more tablets aspirin use ris es concomitantly. Table 2. Aspirin use in a clinical trial of nutrient supplements, by age Age (years) No use Intermittent use Consistent use No. % No. % No. % -: 50 54 82 8 12 4 6 50-59 170 79 26 12 19 9 60-69 277 72 51 13 59 15 2: 70 92 74 13 10 20 16 From Greenberg et al. (1993) 4S IARC Handbooks of Cancer Prevention 3. Metabolism, Kinetics and Genetic (Spenney, 1978), liver (Ali & Kaur, 1983) and Variation erythrocytes (Costello et al.i 1984). Salicylic acid is further metabolized in the liver and kid- 3.1 Human studies neys into its glycine conjugate salicyluric acid 3. 1. 1 Metabolism and its glucuronic acid conjugates, salicyl phe- The metabolism of acetylsalicylic acid (aspirin) nolic glucuronide and salicyl acyl glucuronide.
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