DOCSLIB.ORG

Nonsteroidal Antiinflammatory Drugs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nonsteroidal Antiinflammatory Drugs Analgesics are drugs that relieve pain without signifi cantly altering consciousness. They relieve pain without affecting its cause. Analgesics Opioid Non-opioid (Narcotic analgesics) (Nonsteroidal antiinfl ammatory drugs) NONSTEROIDAL ANTIINFLAMMATORY DRUGS Classifi cation 1. Nonselective cyclooxygenase (COX) inhibitors a. Salicylates: Aspirin b. Propionic acid derivatives: Ibuprofen, ketoprofen, naproxen, fl urbiprofen. c. Acetic acid derivatives: Diclofenac, aceclofenac. d. Fenamic acid derivatives: Mefenamic acid. e. Pyrrolo–pyrrole derivatives: Ketorolac, etodolac. f. Oxicam derivatives: Piroxicam, tenoxicam. g. Indole derivatives: Indomethacin. 2. Preferential COX-2 inhibitors: Nimesulide, meloxicam, nabumetone. 3. Highly selective COX-2 inhibitors: Etoricoxib, parecoxib, lumiracoxib. 4. Analgesic—antipyretics with poor antiinfl ammatory effect: Paracetamol, nefopam. 1 Ch-07_edtd.indd 203 3/19/2014 10:24:18 AM Mechanism of action COX is the enzyme responsible for the biosynthesis of various prostaglandins. There are two well- recognized isoforms of COX: COX-1 and COX-2. COX-1 is constitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have important role in many tissues (Fig. 7.2, p. 201). COX-2 is induced during infl ammation by cytokines and endotoxins, and is responsible for the production of prostanoid mediators of infl ammation. Aspirin and most of the nonsteroidal antiinfl ammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 isoforms, thereby decrease prostaglandin and thromboxane synthesis. The antiinfl ammatory effect of NSAIDs is mainly due to inhibition of COX-2. Aspirin causes irreversible inhibition of COX. Rest of the NSAIDs cause reversible inhibition of the enzyme. Pharmacological actions of aspirin and other NSAIDs Aspirin (acetylsalicylic acid) is the prototype drug. The other nonselective NSAIDs vary mainly in their potency, analgesic, antiinfl ammatory effects and duration of action. 1. Analgesic effect: NSAIDs are mainly used for relieving musculoskeletal pain, dysmenorrhoea and pain associated with infl ammation or tissue damage. Analgesic effect is mainly due to peripheral inhibition of PG production. They also increase pain threshold by acting at subcortical site. These drugs relieve pain without causing sedation, tolerance or drug dependence. 2. Antipyretic effect: The thermoregulatory centre is situated in the hypothalamus. Fever occurs when there is a disturbance in hypothalamic thermostat. NSAIDs reset the hypothalamic thermostat and reduce the elevated body temperature during fever. They promote heat loss by causing cutaneous vasodilatation and sweating. They do not affect normal body temperature. The antipyretic effect is mainly due to inhibition of PGs in the hypothalamus. 3. Antiinfl ammatory effect: Antiinfl ammatory effect is seen at high doses (aspirin: 4–6 g/day in divided doses). These drugs produce only symptomatic relief. They suppress signs and symptoms of infl ammation such as pain, tenderness, swelling, vasodilatation and leukocyte infi ltration but do not affect the progression of underlying disease. The antiinfl ammatory action of NSAIDs is mainly due to inhibition of PG synthesis at the site of injury. They also affect other mediators of infl ammation (bradykinin, histamine, serotonin, etc.), thus inhibit granulocyte adherence to the damaged vasculature. NSAIDs also cause modulation of T-cell function, stabilization of lysosomal membrane and inhibition of chemotaxis. 4. Antiplatelet (antithrombotic) effect: Aspirin in low doses (50–325 mg/day) irreversibly inhibits platelet TXA2 synthesis and produces antiplatelet effect, which lasts for 8–10 days, i.e. the life-time of platelets. Aspirin in high doses (2–3 g/day) inhibits both PGI2 and TXA2 synthesis; hence benefi cial effect of PGI2 is lost. Aspirin should be withdrawn 1 week prior to elective surgery because of the risk of bleeding. PGI2 (PGI2 causes vasodilatation and inhibits platelet aggregation) Aspirin (2–3 g/day) TXA2 (TXA2 causes vasoconstriction and promotes platelet aggregation) Low-dose aspirin (50–325 mg) 2 Ch-07_edtd.indd 204 3/19/2014 10:24:18 AM 5. Acid–base and electrolyte balance: In therapeutic doses, salicylates cause respiratory alkalosis, which is compensated by excretion of alkaline urine (compensated respiratory alkalosis). In toxic doses, the respiratory centre is depressed and can lead to respiratory acidosis. Later, there is uncompensated metabolic acidosis. 6. Gastrointestinal tract (GIT): Aspirin irritates the gastric mucosa and produces nausea, vomiting and dyspepsia. The salicylic acid formed from aspirin also contributes to these effects. Aspirin also stimulates chemoreceptor trigger zone (CTZ) and produces vomiting (Fig. 7.4). Increase in Aspirin Inhibits PGs in the gastric mucosa HCl production Loss of Gastric irritation, protective action peptic ulcer Acidic Exists in Aspirin Enters the pH of unionized form mucosal cell stomach pH 7.1 Acute ulcers Ionized and Erosive gastritis becomes indiffusible Haemorrhage Aspirin CTZ PGs ↑HCl Salicylic acid Fig. 7.4 Action of aspirin on stomach and CTZ. , Stimulation; , inhibition; PGs, prostaglandins. 7. Cardiovascular system (CVS): Prolonged use of aspirin and other NSAIDs causes sodium and water retention. They may precipitate congestive cardiac failure (CCF) in patients with low cardiac reserve. They may also decrease the effect of antihypertensive drugs. 8. Urate excretion: Salicylates, in therapeutic doses, inhibit urate secretion into the renal tubules and increase plasma urate levels. In high doses, salicylates inhibit the reabsorption of uric acid in renal tubules and produce uricosuric effect. Pharmacokinetics Salicylates are rapidly absorbed from the upper GI tract. They are highly bound to plasma proteins but the binding is saturable. Salicylates are well distributed throughout the tissues and body fl uids; metabolized in liver by glycine and glucuronide conjugation. In low doses, elimination follows fi rst-order kinetics and with high doses as the metabolizing enzymes get saturated, it switches over to zero-order 3 Ch-07_edtd.indd 205 3/19/2014 10:24:18 AM kinetics. After this, an increase in salicylate dosage increases its plasma concentration disproportionately and severe toxicity can occur. Alkalinization of urine increases the rate of excretion of salicylates. Dosage regimen for aspirin Analgesic dose: 2–3 g/day in divided doses. Antiinfl ammatory dose: 4–6 g/day in divided doses. Antiplatelet dose: 50–325 mg/day (low-dose aspirin). Adverse effects 1. GIT: Nausea, vomiting, dyspepsia, epigastric pain, acute gastritis, ulceration and GI bleeding. Ulcerogenic effect is the major drawback of NSAIDs, which is prevented/minimized by taking: a. NSAIDs after food. b. proton pump inhibitors/H2-blockers/misoprostol with NSAIDs. c. buffered aspirin (preparation of aspirin with antacid). d. selective COX-2 inhibitors. 2. Hypersensitivity: It is relatively more common with aspirin. The manifestations are skin rashes, urticaria, rhinitis, bronchospasm, angioneurotic oedema and rarely anaphylactoid reaction. Bronchospasm (aspirin-induced asthma) is due to increased production of leukotrienes. Incidence of hypersensitivity is high in patients with asthma, nasal polyps, recurrent rhinitis or urticaria. Therefore, aspirin should be avoided in such patients. 3. In people with G6PD defi ciency, administration of salicylates may cause haemolytic anaemia. 4. Prolonged use of salicylates interferes with action of vitamin K in the liver decreased synthesis of clotting factors (hypoprothrombinaemia) predisposes to bleeding (can be treated by administration of vitamin K). 5. Reye’s syndrome: Use of salicylates in children with viral infection may cause hepatic damage with fatty infi ltration and encephalopathy—Reye’s syndrome. Hence, salicylates are contraindicated in children with viral infection. 6. Pregnancy: These drugs inhibit PG synthesis, thereby delay onset of labour and increase chances of postpartum haemorrhage. In the newborn, inhibition of PG synthesis results in premature closure of the ductus arteriosus. 7. Analgesic nephropathy: Slowly progressive renal failure may occur on chronic use of high doses of NSAIDs. Renal failure is usually reversible on stoppage of therapy but rarely, NSAIDs may cause irreversible renal damage. Salicylism Salicylate intoxication may be mild or severe. The mild form is called salicylism. The symptoms include headache, tinnitus, vertigo, confusion, nausea, vomiting, diarrhoea, sweating, hyperpnoea, electrolyte imbalance, etc. These symptoms are reversible on stoppage of therapy. Acute Salicylate Poisoning Manifestations are vomiting, dehydration, acid–base and electrolyte imbalance, hyperpnoea, restlessness, confusion, coma, convulsions, cardiovascular collapse, pulmonary oedema, hyperpyrexia and death. 4 Ch-07_edtd.indd 206 3/19/2014 10:24:18 AM Treatment There is no specifi c antidote for salicylate poisoning. Treatment is symptomatic. Hospitalization. Gastric lavage followed by administration of activated charcoal (activated charcoal adsorbs the toxic material—physical antagonism). Maintain fl uid and electrolyte balance. Correct acid–base disturbances. Intravenous sodium bicarbonate to treat metabolic acidosis. It also alkalinizes the urine and enhances renal excretion of salicylates (since salicylates exist in ionized form in alkaline pH). External cooling. Haemodialysis in severe cases. Vitamin K1 and blood transfusion, if there is bleeding. Clinical uses of NSAIDs (For basis and explanation,
Load more

Recommended publications
  • Synthesis and Pharmacological Evaluation of Fenamate Analogues: 1,3,4-Oxadiazol-2-Ones and 1,3,4- Oxadiazole-2-Thiones
    Scientia Pharmaceutica (Sci. Pharm.) 71,331-356 (2003) O Osterreichische Apotheker-Verlagsgesellschaft m. b.H., Wien, Printed in Austria Synthesis and Pharmacological Evaluation of Fenamate Analogues: 1,3,4-Oxadiazol-2-ones and 1,3,4- Oxadiazole-2-thiones Aida A. ~l-~zzoun~'*,Yousreya A ~aklad',Herbert ~artsch~,~afaaA. 2aghary4, Waleed M. lbrahims, Mosaad S. ~oharned~. Pharmaceutical Sciences Dept. (Pharmaceutical Chemistry goup' and Pharmacology group2), National Research Center, Tahrir St. Dokki, Giza, Egypt. 3~nstitutflir Pharmazeutische Chemie, Pharrnazie Zentrum der Universitilt Wien. 4~harmaceuticalChemistry Dept. ,' Organic Chemistry Dept. , Helwan University , Faculty of Pharmacy, Ein Helwan Cairo, Egypt. Abstract A series of fenamate pyridyl or quinolinyl analogues of 1,3,4-oxadiazol-2-ones 5a-d and 6a-r, and 1,3,4-oxadiazole-2-thiones 5e-g and 6s-v, respectively, have been synthesized and evaluated for their analgesic (hot-plate) , antiinflammatory (carrageenin induced rat's paw edema) and ulcerogenic effects as well as plasma prostaglandin E2 (PGE2) level. The highest analgesic activity was achieved with compound 5a (0.5 ,0.6 ,0.7 mrnolkg b.wt.) in respect with mefenamic acid (0.4 mmollkg b.wt.). Compounds 6h, 61 and 5g showed 93, 88 and 84% inhibition, respectively on the carrageenan-induced rat's paw edema at dose level of O.lrnrnol/kg b.wt, compared with 58% inhibition of mefenamic acid (0.2mmoll kg b.wt.). Moreover, the highest inhibitory activity on plasma PGE2 level was displayed also with 6h, 61 and 5g (71, 70,68.5% respectively, 0.lmmolkg b.wt.) compared with indomethacin (60%, 0.01 mmolkg b.wt.) as a reference drug.
    [Show full text]
  • United States Patent (19) 11 4,360,518 Rovee Et Al
    United States Patent (19) 11 4,360,518 Rovee et al. 45) Nov. 23, 1982 54 TOPICAL ANTI-INFLAMMATORY DRUG Primary Examiner-Stanley J. Friedman THERAPY . 57) ABSTRACT 75) Inventors: David T. Rovee, Bridgewater; John A pharmaceutical composition for topical treatment of R. Marvel; James A. Mezick, both of cutaneous disorders or disruptions characterized by East Brunswick, all of N.J. skin inflammation or hyperproliferative epidermal ac 73) Assignee: Johnson & Johnson, New Brunswick, tivity comprises the combination of a topically active N.J. anti-inflammatory corticosteroid and a non-steroidal 21 Appl. No.: 244,569 anti-inflammatory agent which is an inhibitor of prosta glandin synthetase selected from the group consisting of 22 Filed: Mar. 17, 1981 the hydratropic acid derivatives; acetylsalicylic acid; the pyrazolone derivatives; the fenamic acid deriva Related U.S. Application Data tives; the aroyl-substituted pyrroles and the substituted 60) Division of Ser. No. 64,311, Aug. 6, 1979, abandoned, arylacetohydroxamic acids in a pharmaceutically ac which is a division of Ser. No. 788,453, Apr. 20, 1977, ceptable topical vehicle. Treatment of above cutaneous Pat. No. 4,185, 100, which is a continuation-in-part of disorders may also be effected by concurrent therapy Ser. No. 685,942, May 13, 1976, abandoned. using separate applications of corticosteroid and non 51) Int. Cl. ...................... A61K 31/19; A61K 31/56 steroid. (52) U.S. Cl. ..................................... 424/240; 424/317 58) Field of Search ................................ 424/317, 240 18 Claims, No Drawings 4,360,518 1 2 Ziboh, V. A. and Snyder, D. S. 1974 Naturally occur TOPICAL ANTI-NFLAMMATORY ORUG ring and synthetic inhibitors of prostaglandin synthetase THERAPY of the skin.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,221,377 B1 Meyer (45) Date of Patent: Apr
    USOO6221377B1 (12) United States Patent (10) Patent No.: US 6,221,377 B1 Meyer (45) Date of Patent: Apr. 24, 2001 (54) ADMINISTRATION MEDIA FOR (56) References Cited ANALGESIC, ANTI-INFLAMMATORY AND ANT-PYRETC DRUGS CONTAINING FOREIGN PATENT DOCUMENTS NITROUS OXDE AND PHARMACEUTICAL 2 277 264 10/1994 (GB). COMPOSITIONS CONTAINING SUCH MEDIA AND DRUGS OTHER PUBLICATIONS (75) Inventor: Petrus Johannes Meyer, Randburg Chemical ABstracts AN 1985:464783, Hertz et al., Jan. (ZA) 1985.* Chemical Abstracts AN 1978:44978, Berkowitz et al., Jan. (73) Assignee: Pitmy International N.V., Bonaire 1977.* (NL) International Publication No. WO93/25213, published Dec. 23, 1993. (*) Notice: Subject to any disclaimer, the term of this Mikrochim. Acta, vol. 2, No. 5-6, 1980 pp. 464–474, Stahl patent is extended or adjusted under 35 et al., Extraction of natural Substances using Supercritical U.S.C. 154(b) by 0 days. and liquified gases. (21) Appl. No.: 09/068,543 Reynolds J.E.F. et al., “Martindale', 1989, The Pharmaceu tical Press. (22) PCT Filed: Nov. 13, 1996 Science, vol. 194, No. 4268, 1976, pp. 967–968, Berkowitz (86) PCT No.: PCT/IB96/01366 et al., "Nitrous oxide “analgesia': resemblance to opiate action'. S371 Date: May 13, 1998 Steinegger et al., “Lehrbuch der Pharmakognosie und Phy S 102(e) Date: May 13, 1998 topharmazie', Edition 4, 1988. (87) PCT Pub. No.: WO97/17978 * cited by examiner PCT Pub. Date: May 22, 1997 Primary Examiner Jyothsna Venkat (30) Foreign Application Priority Data ASSistant Examiner-Grace Hsu (74) Attorney, Agent, or Firm-Arent Fox Kintner Plotkin Nov. 13, 1995 (ZA) ...................................................
    [Show full text]
  • Objective Salicylate Propionic Acid Derivatives Acetic Acid
    Semester-IV Sub Name-medicinal chemistry-I (sub code-BP-402T) Objective Sodium salicylate, Aspirin, Mefenamic acid*, Meclofenamate, Indomethacin, Sulindac, Tolmetin, Zomepriac, Diclofenac, Ketorolac, Ibuprofen*, Naproxen, Piroxicam, Phenacetin, Acetaminophen, Antipyrine, Phenylbutazone. 1. INTRODUCTION A drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti- inflammatory agents block certain substances in the body that cause inflammation. They are used to treat many different conditions. Some anti-inflammatory agents are being studied in the prevention and treatment of cancer. 1.1 CLASSIFICATION NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. Salicylate • Aspirin (acetylsalicylic acid) • Diflunisal (Dolobid) • Salicylic acid and its salts Propionic acid derivatives • Ibuprofen • Dexibuprofen • Naproxen • Fenoprofen • Ketoprofen • Dexketoprofen Acetic acid derivatives • Indomethacin • Tolmetin • Sulindac • Ketorolac • Diclofenac • Aceclofenac • Nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid group) Enolic acid (oxicam) derivatives • Piroxicam • Meloxicam • Tenoxicam • Droxicam • Lornoxicam • Isoxicam (withdrawn from market 1985) • Phenylbutazone Anthranilic acid derivatives (fenamates) The following NSAIDs are
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,852,615 B1 Harrison Et Al
    USOO8852615B1 (12) United States Patent (10) Patent No.: US 8,852,615 B1 Harrison et al. (45) Date of Patent: *Oct. 7, 2014 (54) CLEAR, GREASELESS SKIN-CARE 4,935,224 A 6, 1990 Russo et al. COMPOSITIONS 4,997,853. A 3, 1991 Bernstein 5,013,726 A 5/1991 Ivy et al. 5,082,661 A 1/1992 Melnik et al. (75) Inventors: James Jeffries Harrison, West Hills, 5,124,320 A 6/1992 Ivy et al. CA (US); Nohemi Harrison, West Hills, 5,607,980 A 3, 1997 McAtee et al. CA (US) 5,759,529 A 6/1998 LeGrow et al. 5,856,361 A 1/1999 Holt et al. 5,916,548 A 6/1999 Hutchins et al. (73) Assignee: Chemsil Silicones, Inc., Chatsworth, CA 5,993,837 A 11/1999 Calello et al. (US) 6,103,266 A 8/2000 Tapolsky et al. 6,106,820 A 8/2000 Morrissey et al. (*) Notice: Subject to any disclaimer, the term of this 6,124,490 A 9/2000 Gormley et al. patent is extended or adjusted under 35 6,296,880 B1 10/2001 Murad U.S.C. 154(b) by 0 days. 6,338,855 B1 1/2002 Albacarys et al. 6,348,501 B1 2/2002 Holt et al. This patent is Subject to a terminal dis 6,372,234 B1 4/2002 Deckers et al. claimer. 6,383,523 B1 5, 2002 Murad 6,384,023 B2 5/2002 Singleton et al. 6,403,069 B1 6/2002 Chopra et al. (21) Appl.
    [Show full text]
  • Solubility and Dissolution Thermodynamic Data of Mefenamic Acid Crystals in Different Classes of Organic Solvents
    Article pubs.acs.org/jced Solubility and Dissolution Thermodynamic Data of Mefenamic Acid Crystals in Different Classes of Organic Solvents Siti K. Abdul Mudalip,†,‡ Mohd R. Abu Bakar,*,§ Parveen Jamal,† and Fatmawati Adam‡ † Department of Biotechnology Engineering, Kulliyyah of Engineering, International Islamic University Malaysia, 50728 Kuala Lumpur, Malaysia ‡ Department of Chemical Engineering, Faculty of Chemical Engineering & Natural Resources, University Malaysia Pahang, Gambang, 26300 Kuantan, Pahang, Malaysia § Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, Bandar Indera Mahkota, 25200 Kuantan, Pahang, Malaysia ABSTRACT: Different classes of solvents provide different polarity values, which influence the solubility of pharmaceutical solids. In this article, the solubility of mefenamic acid in different classes of organic solvents, including polar protic, dipolar aprotic, and apolar aprotics at a range of temperatures from (298 to 323) K are reported. It has been found that mefenamic acid shows high solubility in dipolar aprotic solvents (N,N-dimethylacetamide, N,N-dimethylformamide, ethyl acetate, and propanone), moderate solubility in polar protic solvents (ethanol and propan-2-ol), and poor solubility in apolar aprotic solvents (hexane, heptane, and cyclohexane) and water. ■ INTRODUCTION gravimetrically12 or using spectroscopy.13 Some variations of the 2-[(2,3-Dimethylphenyl)amino]benzoic acid (C H NO , me- technique are also available, which are described in detailed 15 15 2 elsewhere.11,14 Another experimental technique for the solubility fenamic acid) is a widely used nonsteroidal anti-inflammatory determination involves heating up a suspension of solid and and analgesic agent for the treatment of pain caused by 1,2 solvent to dissolution and detecting the clear point, which is menstrual disorders.
    [Show full text]
  • Vol-7 (1) 2006 BSM.Pmd
    J MEDICINE 2006; 7 : 20-31 REVIEW ARTICLES NON STEROIDAL ANTI INFLAMMATORY DRUGS- AN OVERVIEW M MATIUR RAHMAN1, MD. BILLAL ALAM2, LT. COL. MD. AZIZUL ISLAM3, AKM AMINUL HAQUE4 Epidemiology from the cell membrane phospholipids by a cascade of More than 20 million Americans use various different enzymes. The sequence starts with release of nonsteroidal anti-inflammatory drugs (NSAIDs) on a arachidonic acid from the cell membrane by regular basis, making this class of drugs one of the Phospholipase-A2. Arachidonic acid is then converted most commonly used. Approximately 1 to 2 percent by cyclo oxygenase to prostaglandins, prostacyclin, and of patients taking NSAIDS will develop serious thromboxanes 8. The Cox-1 gene was cloned and gastrointestinal toxicity, which has resulted in 100,000 sequenced in 1988 and in 1991, a second cyclooxygenase to 400,000 hospitalizations per year in the United gene was identified. Celecoxib, the first Cox-2 selective States at a cost of over 2 billion dollars 1-3. In the NSAID got the US FDA approval in 19988-9. United States, 10 to 20,000 peoples died every year of NSAID complications. There are at least 2600 excess Mechanism of action deaths in the United States each year related to Cyclooxygenase inhibition – The primary effect of NSAIDs gastrointestinal toxic reactions in patients with is to inhibit cyclooxygenase (prostaglandin synthase), Rheumatoid Arthritis (RA) who are treated with thereby impairing the ultimate transformation of NSAIDs 4-5. A variety of NSAIDs are readily available arachidonic acid to prostaglandins, prostacyclin, and (at least 20 in the United States and more elsewhere) thromboxanes.
    [Show full text]
  • Crystallisation and Physicochemical Property Characterisation of Conformationally-Locked Co-Crystals of Fenamic Acid Derivatives
    Electronic Supplementary Material (ESI) for CrystEngComm. This journal is © The Royal Society of Chemistry 2015 Crystallisation and physicochemical property characterisation of conformationally-locked co-crystals of fenamic acid derivatives K. E. Wittering,a,b L. R. Agnew,a,b A. R. Klapwijk,a,b K. Robertson,a,b A. J. P. Cousen,a,b D. L. Cruickshank, *a and C. C. Wilson*a a Department of Chemistry, University of Bath, Bath, BA2 7AY b Engineering and Physical Sciences Research Council (EPSRC) Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC), University of Bath, Bath, BA2 7AY [email protected], [email protected] Supporting information Table S1. All variables investigated during the co-crystal screening studies* Crystallisation Ratio API Co-former Solvent temperature (API:co-former) (°C) Fenamic acid Urea§ 1:1 Methanol 4 Flufenamic acid Oxalic acid 2:1 Isopropanol 18 Mefenamic acid Isonicotinamide 1:2 Dimethylformamide 30 Tolfenamic acid Nicotinic acid§ Ethanol 50 4-aminobenzoic acid Acetone 2-aminobenzoic acid Tetrahydrofuran Pyridoxine§ Isonicotinic acid hydrazide§ 4,4’-bipiridyl 2,2’-bipridyl 2-aminopyridine §Classified as GRAS by the Select Committee on GRAS Substances (SCOGS) *Note. The crystallisations were prepared using the minimal solvent required for dissolution with the aid of a sonic bath (30 °C). All combinations of API, co-former and ratio stated in Table S1 were tested with one or more of the solvents listed dependant on solubility, so not all possible solvents were used for each combination. The maximum crystallisation temperature used was appropriate to the boiling point of the solvent used.
    [Show full text]
  • Protection Against Peroxynitrite Dependent Tyrosine Nitration and A1
    Annals ofthe Rheumatic Diseases 1996; 55: 383-387 383 Protection against peroxynitrite dependent Ann Rheum Dis: first published as 10.1136/ard.55.6.383 on 1 June 1996. Downloaded from tyrosine nitration and a1-antiproteinase inactivation by some anti-inflammatory drugs and by the antibiotic tetracycline Matthew Whiteman, Harparkash Kaur, Barry Halliwell Abstract physiological pH to give a range of noxious Objective-To examine in vitro the ability products with reactivities resembling those of of several drugs to protect against del- hydroxyl radicals (OH), nitrogen dioxide eterious effects of peroxynitrite, a cyto- (NO2%), and nitronium ion (NO2+).8 toxic agent formed by reaction of nitric Addition of peroxynitrite to tissues and oxide with superoxide radical, that may be biological fluids leads to nitration of aromatic generated in the rheumatoid joint and amino acid residues, and the presence of these could cause joint damage. may be a 'marker' of peroxynitrite mediated Methods-The ability of several drugs to (NO" dependent) damage in vivo.6 9-11 Indeed, protect against such possible toxic actions nitrotyrosine is present in plasma and synovial ofperoxynitrite as inactivation of Gl-anti- fluid from patients with RA, but it was not proteinase and nitration of tyrosine was detected in healthy control subjects.'2 Nitration evaluated. of tyrosine residues on proteins may interfere Results-Most non-steroidal anti-inflam- with cell signal transduction by tyrosine matory drugs were moderately (indo- phosphorylation/dephosphorylation.'3 Peroxy-
    [Show full text]
  • Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti- Inflammatory Drugs: a Review
    Send Orders for Reprints to [email protected] 326 Current Drug Metabolism, 2014, 15, 326-343 Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti- Inflammatory Drugs: A Review Victoria Rollason1,*, Caroline Flora Samer1,2, Youssef Daali1,2 and Jules Alexandre Desmeules1,2 1Division of Clinical Pharmacology and Toxicology, Multidisciplinary Pain Centre, University Hospitals of Geneva and University of Geneva, Switzerland; 2Swiss Centre for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used drugs, either on prescription or over-the- counter (OTC). Their daily dosage is based on randomised controlled trials and an empirical clinical assessment of their efficacy and tox- icity that allows dose adjustment. The individual response can however be altered by environmental and genetic pharmacokinetic and pharmacodynamic factors. This review summarizes the available pharmacogenetic data that explains part of the variability in response and occurrence of adverse drug reactions to NSAIDs treatment, with a thorough focus on CYP2C9, uridine diphosphate glucuronosyl- transferases (UGTs) and cyclooxygenases (COX1 and COX2). Other polymorphisms that are currently being studied and could also ex- plain the interindividual variability in the efficacy and safety of NSAIDs will also be considered. Keywords: COX, CYP2C8, CYP2C9, genetic polymorphism, NSAIDs, PTGS, UDP glucuronsyltransferases, UGT. INTRODUCTION efficacy and toxicity of NSAIDs have been reported for only some Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the of these PK and PD steps. We will evaluate in this review the class of drugs most commonly taken by patients, either on prescrip- pharmacogenetic data available for NSAIDs and their potential tion or over-the-counter (OTC).
    [Show full text]
  • Pms-IBUPROFEN
    PRODUCT MONOGRAPH Prpms-IBUPROFEN Ibuprofen Tablets, USP 600 mg tablets Nonsteroidal Anti-Inflammatory Drug, Analgesic, Antipyretic Agent Pharmascience Inc Date of Revision: 6111 Royalmount Avenue August 21, 2015 Montreal, Quebec H4P 2T4 www.pharmascience.com Submission Control No: 183725 pms-IBUPROFEN Product Monograph Page 1 of 36 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION ......................................................... 3 SUMMARY PRODUCT INFORMATION ........................................................................ 3 INDICATIONS AND CLINICAL USE.............................................................................. 3 CONTRAINDICATIONS ................................................................................................... 4 WARNINGS AND PRECAUTIONS ................................................................................. 5 ADVERSE REACTIONS ................................................................................................. 13 DRUG INTERACTIONS .................................................................................................. 16 DOSAGE AND ADMINISTRATION .............................................................................. 19 OVERDOSAGE ................................................................................................................ 19 ACTION AND CLINICAL PHARMACOLOGY ............................................................ 20 STORAGE AND STABILITY ........................................................................................
    [Show full text]
  • And Stereoselective Hydroxylation of Α-Ionone
    VU Research Portal Engineered cytochrome P450 BM3 mutants as biocatalysts for metabolite production: Applications in biotechnology and toxicology Venkataraman, H. 2014 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Venkataraman, H. (2014). Engineered cytochrome P450 BM3 mutants as biocatalysts for metabolite production: Applications in biotechnology and toxicology. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 06. Oct. 2021 ENGINEERED CYTOCHROME P450 BM3 MUTANTS AS BIOCATALYSTS FOR METABOLITE PRODUCTION: APPLICATIONS IN BIOTECHNOLOGY AND TOXICOLOGY Harini Venkataraman Engineered cytochrome P450 BM3 mutants as biocatalysts for metabolite production: applications in biotechnology and toxicology Harini Venkataraman Printed by Ipskamp Drukkers Cover design by Dhwajal Chavan Copyright Harini Venkataraman, Amsterdam 2014. All rights reserved. No part of this thesis may be reproduced in any form or by any means without permission from the author.
    [Show full text]