DOCSLIB.ORG

Synergism Between Paracetamol and Nonsteroidal Anti-Inflammatory

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synergism Between Paracetamol and Nonsteroidal Anti-Inflammatory Pain 121 (2006) 22–28 www.elsevier.com/locate/pain Synergism between paracetamol and nonsteroidal anti-inflammatory drugs in experimental acute pain Hugo F. Miranda a,*, Margarita M. Puig b, Juan Carlos Prieto a, Gianni Pinardi a a Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Clasificador 70.000, Santiago 7, Chile b Department of Anesthesiology, Hospital del Mar, Paseo Marı´timo 25, 08003 Barcelona, Spain Received 9 June 2005; received in revised form 3 November 2005; accepted 21 November 2005 Abstract The antinociception induced by the intraperitoneal coadministration of combinations of paracetamol with the nonsteroidal anti- inflammatory drugs (NSAIDs) diclofenac, ibuprofen, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and pir- oxicam was studied by isobolographic analysis in the acetic acid abdominal constriction test of mice (writhing test). The effective dose that produced 50% antinociception (ED50) was calculated from the log dose–response curves of fixed ratio combinations of paracetamol with each NSAID. By isobolographic analysis, this ED50 was compared to the theoretical additive ED50 calculated from the ED50 of paracetamol and of each NSAID alone obtained from ED50 dose–response curves. As shown by isobolographic analysis, all the combinations were synergistic, the experimental ED50s being significantly smaller than the theoretically calculated ED50s. The results of this study demonstrate potent interactions between paracetamol and NSAIDs and validate the clinical use of combinations of these drugs in the treatment of pain conditions. Ó 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. Keywords: Antinociception; NSAIDs; Paracetamol; Synergy; Abdominal constriction test; Writhing test; Isobologram 1. Introduction The antinociceptive action of nonsteroidal anti-in- flammatory drugs (NSAIDs) is primarily due to the The combination of analgesics of proven efficacy is a inhibition of prostaglandin biosynthesis through the strategy intended to achieve one or more therapeutic inhibition of cyclooxygenase enzymes: COX-1 (constitu- goals, such as facilitating patient compliance, simplifying tive) and COX-2 (inducible in inflammatory processes), prescribing, improving efficacy without increasing even if alternative mechanisms have to be considered adverse effects or decreasing adverse effects without loss (Mitchell and Warner, 1999; Smith et al., 2000; Miranda of efficacy (Raffa, 2001; Hyllested et al., 2002). In certain et al., 2002; Warner and Mitchell, 2004). However, the cases, the coadministration of antinociceptive agents absolute separation between the physiological and path- results in synergistic effects and the doses of the individ- ological roles of COX-1 and COX-2 is becoming less ual drugs can be substantially reduced (Maves et al., tenable and indeed their activities overlap to a consider- 1994; Salazar et al., 1995; Fairbanks and Wilcox, 1999; able degree (Wallace, 1999). On the other hand, the Kolesnikov et al., 2002; Miranda and Pinardi, 2004). mechanism of action of one of the most widely used analgesics, paracetamol or acetaminophen, remains largely unknown and at most the drug is considered to be an atypical NSAID, since it is a weak inhibitor of * Corresponding author. Tel.: +56 2 678 6237; fax: +56 2 737 2783. COXs (Botting, 2003). The following mechanisms have E-mail address: [email protected] (H.F. Miranda). been postulated to explain paracetamol-induced 0304-3959/$20.00 Ó 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2005.11.012 H.F. Miranda et al. / Pain 121 (2006) 22–28 23 analgesia: selective inhibition of cyclooxygenase activity 2.3. Control animals in the CNS, interaction with spinal 5-HT3 receptors, interference with spinal substance P receptors or Physiological salt solution (10 mL/kg) was injected intra- inhibition of neurons excited by substance P, activation peritoneally (i.p.) or given orally and control animals were of suprasegmental descending inhibitory pathways, run interspersed concurrently with the drug treatments, which prevented the controls being run on a single group of mice at increase in pituitary b-endorphin secretion, direct effects one time (19.7 ± 0.28, n = 92 i.p.; 20.1 ± 0.33, n = 12 p.o.). on neuronal membrane potentials (Bannwarth et al., 1995; Pelissier et al., 1995; Pini et al., 1996; Raffa and 2.4. Protocol Codd, 1996; Breivik et al., 1999). NSAIDs and paracetamol are drugs widely used to Dose–response curves for the antinociceptive effect of dic- treat moderate to mild pain, but they are often inad- lofenac, ibuprofen, ketoprofen, meloxicam, metamizol, equate against severe pain. Clinical studies on patients naproxen, nimesulide, paracetamol, parecoxib, and piroxicam with musculoskeletal conditions, dental pain or post- were obtained using at least six animals at each of at least operative pain have shown that combinations of para- four doses. The drugs were injected intraperitoneally. Dose– cetamol and NSAIDs may provide additive pain-relief response curves were also obtained by the oral administration (Altman, 2004). However, a detailed evaluation of dif- of paracetamol and diclofenac. A least-squares linear regres- sion analysis of the log dose–response curves allowed the cal- ferent combinations of paracetamol with commonly culation of the dose that produced 50% of antinociception used NSAIDs has not been reported. The purpose (ED50) for each drug. A dose–response curve was also of the present study was to assess the nature of the obtained by the intraperitoneal coadministration of paraceta- interaction between the systemic administration of mol with each NSAID in fixed ratio combinations of frac- combinations of paracetamol and several NSAIDs in tions of their respective ED50 values: 1/2, 1/4, 1/8, 1/16 a rodent model of visceral pain. A broad number of (ratio values given in Table 2). A dose–response curve for clinical relevant NSAIDs are included because they the combination of paracetamol and diclofenac administered are the most frequently used agents for the treatment orally by gavage was also obtained with the same scheme. of pain (Møiniche et al., 2003; Rømsing and Møini- Isobolographic analysis was used to determine drug interac- che, 2004). tions. The method has been described previously in detail (Miranda et al., 2002). Supra-additivity or synergistic effect is defined as the effect of a drug combination that is higher 2. Materials and methods and statistically different (ED50 significantly lower) than the theoretically calculated equieffect of a drug combination with 2.1. Animals the same proportions. If the ED50s are not statistically differ- ent, the effect of the combination is additive and additivity Male CF-1 mice (28–30 g), housed on a 12 h light–dark means that each constituent contributes with its own potency cycle at 22 ± 2 °C and with access to food and water ad libi- to the total effect. The interaction index was calculated as tum, were used. Experiments were performed in accordance experimental ED50/theoretical ED50. If the value is close to with current Guidelines for The Care of Laboratory Animals 1, the interaction is additive. Values lower than 1 are an indi- and Ethical Guidelines for investigation of experimental pain cation of the magnitude of supra-additive or synergistic inter- approved by the Animal Care and Use Committee of the Fac- actions and values higher than 1 correspond to sub-additive ulty of Medicine, University of Chile. Animals were acclima- or antagonistic interactions (Tallarida, 2001). tized to the laboratory for at least 2 h before testing, were used only once during the protocol and were killed by cervical 2.5. Drugs dislocation immediately after the algesiometric test. The num- ber of animals was kept at a minimum compatible with consis- The drugs were freshly dissolved in a physiological salt solu- tent effects of the drug treatments. tion. Paracetamol was provided by Bristol-Myers-Squibb, France. The NSAIDs were provided by local pharmaceutical 2.2. Measurement of analgesic activity companies: diclofenac by Novartis Chile S.A., ibuprofen by Laboratorio Chile S.A., ketoprofen by Rhone-Poulenc Ror- Analgesic activity was assessed by the acetic acid abdominal er, meloxicam and naproxen by Laboratorios Saval S.A., constriction test (writhing test), a chemical visceral pain model metamizol by Sanderson S.A., nimesulide by Gru¨nenthal (Hayashi and Takemori, 1971). Mice were injected i.p. with Chilena Ltda, parecoxib and piroxicam by Pfizer Chile. 10 mL/kg of 0.6% acetic acid solution 30 min after the i.p. Doses were expressed on the basis of the salts. administration of the drugs, a time at which preliminary exper- iments showed occurrence of the maximum effect. A writhe is 2.6. Statistical analysis characterized by a wave of contraction of the abdominal mus- culature followed by the extension of the hind limbs. The num- Results are presented as means ± SEM or as ED50 values ber of writhes in a 5 min period was counted, starting 5 min with 95% confidence limits (95% CL). Isobolographic calcula- after acetic acid administration. Antinociceptive activity was tions were performed with the program Pharm Tools Pro (ver- expressed as percent inhibition of the usual number of writhes sion 1.27, The McCary Group Inc.), based on Tallarida (2000). observed in control animals in this study. The statistical difference between theoretical and experimental 24 H.F. Miranda et al. / Pain 121 (2006) 22–28 values was assessed by Student’s t test for independent means Table 1 and P values less than 0.05 (P < 0.05) were considered ED50 values and 95% CL for the antinociceptive effect of NSAIDs in significant. the writhing test of mice Drugs ED50 CL ED50 CL 3. Results mg/kg i.p. mg/kg p.o. Ibuprofen 0.8 0.12–6.1 3.1. Antinociception induced by paracetamol and NSAIDs Parecoxib 1.6 1.0–2.6 Meloxicam 6.5 4.9–8.4 Nimesulide 7.6 5.8–9.8 The i.p.
Load more

Recommended publications
  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
    [Show full text]
  • Non-Steroidal Anti-Inflammatory Drugs Alter Nuclear Factor- Κβ in a Class Specific Manner
    Myers MJ et al. Treatment Dev Vet Pract 2020(1): 11-18. 10.33513/TDVP/2001-02 Treatments and Developments: Veterinary Practice OCIMUM Research Article Non-Steroidal Anti-Inflammatory Drugs Alter Nuclear Factor- κβ in A Class Specific Manner Abstract The capacity of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) to affect the NF-κβ dependent pathway was examined. The NSAIDs were co-cultured with RAW 264.7 cells transfected with a plasmid encoding Secreted Embryonic Alkaline Phosphatase (SEAP) under the control of NF-κβ. SEAP production was initiated by stimulating the cells with E. coli derived Lipopolysaccharide Michael J Myers*, Anne J Lewandowski and (LPS). Diclofenac, indomethacin, celecoxib, tolfenamic acid, flufenamic acid, Christine M Deaver and piroxicam inhibited SEAP production. Ketoprofen, phenylbutazone, Center for Veterinary Medicine, Office of Research aspirin, and acetaminophen did not affect SEAP production. TNFα stimulation Division of Applied Veterinary Research, USA of HEK293 cells transfected with a SEAP reporter gene under the control of NF-κβ was used to determine whether the NSAIDs were working directly on Received: 16 June 2020 the NF-κβ pathway or on TLR4 signaling. TNFα stimulated HEK293 cells Accepted: 20 July 2020 showed that diclofenac and flunixin inhibited SEAP production, but aspirin Version of Record Online: 31 July 2020 did not. Meloxicam and diclofenac both inhibited the amount of p65 released after LPS stimulation of the RAW 264.7 cells while flunixin did not affect Citation p65 release. Flunixin had no effect on an NF-κβ gel shift assay. These results demonstrate that NSAIDs in four of the six NSAID families can inhibit NF- Myers MJ, Lewandowski AJ, Deaver CM (2020) κβ pathway, albeit via different points in the pathway.
    [Show full text]
  • The Importance of COX-2 Inhibition for Aspirin Induced Asthma
    S54 Thorax 2000;55 (Suppl 2):S54–S56 Thorax: first published as 10.1136/thorax.55.suppl_2.S54 on 1 October 2000. Downloaded from The importance of COX-2 inhibition for aspirin induced asthma Alan Bennett There have been recent reviews of aspirin “specific” is used here to denote that the activ- induced asthma (AIA),12 the use of the ity is (usually) much greater against COX-2 COX-2 preferential inhibitor nimesulide in than against COX-1. Two drugs with a asthmatic patients intolerant to non-steroidal “preferential” status are nimesulide and mel- anti-inflammatory drugs (NSAIDs),3 and of oxicam, whereas two drugs that probably nimesulide in general.45 This paper discusses deserve the title “specific” are rofecoxib and the importance of inhibiting prostaglandin E2 celecoxib. (PGE2) synthesis in AIA, and the relative Nimesulide (4-nitro-2-phenoxymethane- safety of NSAIDs that preferentially inhibit sulphonanilide) is particularly important in COX-2. AIA because several studies have shown that it Aspirin and other NSAIDs cause broncho- is tolerated by most patients with the disorder constriction in about 10% of asthmatic to about the same extent as paracetamol. This subjects but NSAIDs relieve asthma in about sulphonanilide NSAID, which is eVective in 0.3%.2 This variability helps to show the com- treating a wide spectrum of inflammatory and plexity of the problem. Prostaglandins in painful conditions,7 was first marketed in 1985 human lung are formed by various tissues and and 10 years later it was found to be a cells, including bronchial muscle, epithelium, preferential inhibitor of COX-2.89Because it is and inflammatory cells,12 so the inhibition of not marketed in the USA, Japan, or the UK, prostaglandin formation can have numerous nimesulide is not well known in some parts of eVects.
    [Show full text]
  • Drug Allergies & Cross-Sensitivities
    DRUG ALLERGIES & CROSS-SENSITIVITIES A Presentation for HealthTrust Members June 2, 2020 Vasyl Zbyrak, PharmD, PGY-1Pharmacy Resident Saint Barnabas Medical Center Kristine A. Sobolewski, PharmD, BCPS, Preceptor 2 Speaker & Preceptor Disclosures The presenter and his preceptor have no real or perceived conflicts of interest related to this presentation. Note: This program may contain the mention of suppliers, brands, products, services or drugs presented in a case study or comparative format using evidence-based research. Such examples are intended for educational and informational purposes and should not be perceived as an endorsement of any particular supplier, brand, product, service or drug. 3 Learning Objectives Pharmacists & Nurses: Distinguish the different drug class allergies and their mechanism of action Describe the most common drug allergies and characteristics of an allergic reaction Recommend alternative treatment options based on the drug allergy profile while evaluating the potential risk for the patient 4 Learning Objectives Pharmacy Technicians Identify the characteristics of an allergic reaction and common drug allergies Recognize the names of potentially inappropriate medications based on allergies and cross-sensitivities 5 Patient Case JG is 62 YO female presenting to the ED with pain 9/10. Patient was ordered morphine 4 mg IV push. Pain was relieved, but a rash appeared on her face with some flushing. Patient is not complaining of any other symptoms or shortness of breath. 6 Is the patient experiencing a drug allergy? 7 Adverse Drug Reactions A general term utilized to encompass any unwanted reaction to a medication and are broadly divided into Type A and B reactions Type A Type B • Reactions occurring in most • Drug hypersensitivity that is patients that are common relatively uncommon, rare and predictable and mostly unpredictable • Involves potential overdose, • Involves intolerances, side effects and drug idiosyncrasy, pseudoallergy interactions and drug allergies Source: Celik G, et al.
    [Show full text]
  • Single Dose of Diclofenac Or Meloxicam for Control of Pain, Facial Swelling, and Trismus in Oral Surgery
    Med Oral Patol Oral Cir Bucal. 2016 Jan 1;21 (1):e127-34. Diclofenac versus meloxicam in oral surgery Journal section: Oral Surgery doi:10.4317/medoral.20925 Publication Types: Research http://dx.doi.org/doi:10.4317/medoral.20925 Single dose of diclofenac or meloxicam for control of pain, facial swelling, and trismus in oral surgery Mariana Orozco-Solís 1, Yazmín García-Ávalos 2, Celeste Pichardo-Ramírez 2, Francisco Tobías-Azúa 2, Juan-Ramón Zapata-Morales 3, Othoniel-Hugo Aragon-Martínez 4, Mario-Alberto Isiordia-Espinoza 5 1 DDS, Departamento de Estomatología, Unidad Médica Familiar No. 02, Instituto Mexicano del Seguro Social, Delegación San Luis Potosí, S.L.P., México 2 DDS, Departamento de Investigación y Postgrado, Escuela de Odontología, Universidad Cuauhtémoc, plantel San Luis Poto- sí, S.L.P., México 3 MSc, PhD, Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Guanajuato, México 4 MSc, PhD, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, S.L.P., México 5 DDS, MSc, PhD, Departamento de Farmacología, Facultad de Odontología, Universidad Autónoma de Baja California, Mexi- cali, México Orozco-Solís M, García-Ávalos Y, Pichardo-Ramírez C, Tobías-Azúa F, Zapata-Morales JR, Aragon-Martínez OH, Isiordia-Espinoza MA. Single Correspondence: dose of diclofenac or meloxicam for control of pain, facial swelling, and Facultad de Odontología trismus in oral surgery. Med Oral Patol Oral Cir Bucal. 2016 Jan 1;21 Universidad Autónoma de Baja California (1):e127-34. Calle Zotoluca y Chinampas s/n http://www.medicinaoral.com/medoralfree01/v21i1/medoralv21i1p127.pdf Fraccionamiento Calafia C.P.
    [Show full text]
  • Inflammatory Drugs and the Frequency
    doi: 10.1111/fcp.12463 ORIGINAL Cyclo-oxygenase selectivity and chemical ARTICLE groups of nonsteroidal anti-inflammatory drugs and the frequency of reporting hypersensitivity reactions: a case/noncase study in VigiBase Mohammad Bakhriansyaha,b , Ronald H.B. Meybooma, Patrick C. Souvereina, Anthonius de Boera, Olaf H. Klungela* aDivision of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, PO Box 80082 3508 TB, Utrecht, The Netherlands bDepartment of Pharmacology, Medical Faculty, Lambung Mangkurat University, Jalan Veteran No. 128, 70232 Banjarmasin, South Kalimantan, Indonesia Keywords ABSTRACT a sulfonamide functional group, To date, no reports of hypersensitivity reactions (HSRs) among nonsteroidal chemical groups, anti-inflammatory drugs (NSAIDs) according to cyclo-oxygenase (COX) selectivity cyclo-oxygenase selectivity, and chemical groups have been published in a single study. The present study hypersensitivity reactions, assessed the reporting frequency of HSRs for NSAIDs based on their relative inhibi- nonsteroidal anti-inflamma- tory potency toward COX enzymes and chemical groups, including the presence/ tory drugs, absence of a functional sulfonamide group, in strata observed 5 years after market spontaneous reporting authorization. A case/noncase study was performed among individual case safety reports (ICSRs) with NSAIDs as suspected drugs in VigiBase, the WHO spontaneous Received 9 November 2018; reporting database. Cases were ICSRs mentioning angioedema and anaphylactic/ revised 18 February 2019; anaphylactoid shock conditions, while noncases were ICSRs without HSRs. NSAIDs accepted 8 March 2019 were categorized into (i) NSAIDs with high COX-2 selectivity (coxibs), (ii) noncoxib NSAIDs with COX-2 preference, (iii) NSAIDs with poor selectivity, or (iv) NSAIDs *Correspondence and reprints: with unknown selectivity.
    [Show full text]
  • Metal-Oxicam Coordination Compounds: Structure, Biological Activity and Strategies for Administration
    The Open Crystallography Journal, 2010, 3, 41-53 41 Open Access Metal-Oxicam Coordination Compounds: Structure, Biological Activity and Strategies for Administration Gabriella Tamasi* Department of Chemistry, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy Abstract: The crystal structures for metal-oxicam compounds published since the year 2000 are listed and commented in this review. The structural properties are interpreted in order to look for characteristics that might be significant for possi- ble biological activities, for innovative strategies aimed to administering the metal based drugs in vivo. The relevant bio- logical studies are also listed and commented. The number of structural reports on metal-oxicam compounds that were published up to the year 2000 was five, whereas the number of X-ray structures for the same class of compounds pub- lished since then is fifteen. The efforts carried out on the field during the past decade increased much and involved several research groups all over the world. The predominant metal was CuII, but interest on SnIV increased too, whereas the inter- est on PtII continued for compounds derived from Zeise’s salt. Other metals linked to oxicam ligands were investigated. The X-ray structural studies until ca ten years ago involved metal-piroxicam compounds, only; instead, during these past ten years also metal-meloxicam, -tenoxicam, -isoxicam, and -lornoxicam were studied and reported. The reactivity of cin- noxicam with copper(II)-acetate was also studied and reported. The coordination arrangement around CuII showed a vari- ety of modes that include pseudo-octahedral, -square planar, -square pyramidal. The oxicam coordination mode depends on the ligand, the reaction media and experimental conditions.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • (CD-P-PH/PHO) Report Classification/Justifica
    COMMITTEE OF EXPERTS ON THE CLASSIFICATION OF MEDICINES AS REGARDS THEIR SUPPLY (CD-P-PH/PHO) Report classification/justification of - Medicines belonging to the ATC group M01 (Antiinflammatory and antirheumatic products) Table of Contents Page INTRODUCTION 6 DISCLAIMER 8 GLOSSARY OF TERMS USED IN THIS DOCUMENT 9 ACTIVE SUBSTANCES Phenylbutazone (ATC: M01AA01) 11 Mofebutazone (ATC: M01AA02) 17 Oxyphenbutazone (ATC: M01AA03) 18 Clofezone (ATC: M01AA05) 19 Kebuzone (ATC: M01AA06) 20 Indometacin (ATC: M01AB01) 21 Sulindac (ATC: M01AB02) 25 Tolmetin (ATC: M01AB03) 30 Zomepirac (ATC: M01AB04) 33 Diclofenac (ATC: M01AB05) 34 Alclofenac (ATC: M01AB06) 39 Bumadizone (ATC: M01AB07) 40 Etodolac (ATC: M01AB08) 41 Lonazolac (ATC: M01AB09) 45 Fentiazac (ATC: M01AB10) 46 Acemetacin (ATC: M01AB11) 48 Difenpiramide (ATC: M01AB12) 53 Oxametacin (ATC: M01AB13) 54 Proglumetacin (ATC: M01AB14) 55 Ketorolac (ATC: M01AB15) 57 Aceclofenac (ATC: M01AB16) 63 Bufexamac (ATC: M01AB17) 67 2 Indometacin, Combinations (ATC: M01AB51) 68 Diclofenac, Combinations (ATC: M01AB55) 69 Piroxicam (ATC: M01AC01) 73 Tenoxicam (ATC: M01AC02) 77 Droxicam (ATC: M01AC04) 82 Lornoxicam (ATC: M01AC05) 83 Meloxicam (ATC: M01AC06) 87 Meloxicam, Combinations (ATC: M01AC56) 91 Ibuprofen (ATC: M01AE01) 92 Naproxen (ATC: M01AE02) 98 Ketoprofen (ATC: M01AE03) 104 Fenoprofen (ATC: M01AE04) 109 Fenbufen (ATC: M01AE05) 112 Benoxaprofen (ATC: M01AE06) 113 Suprofen (ATC: M01AE07) 114 Pirprofen (ATC: M01AE08) 115 Flurbiprofen (ATC: M01AE09) 116 Indoprofen (ATC: M01AE10) 120 Tiaprofenic Acid (ATC:
    [Show full text]
  • Incidence of Mucocutaneous Reactions in Children Treated with Niflumic Acid, Other Nonsteroidal Antiinflammatory Drugs, Or Nonopioid Analgesics
    Incidence of Mucocutaneous Reactions in Children Treated With Niflumic Acid, Other Nonsteroidal Antiinflammatory Drugs, or Nonopioid Analgesics Miriam Sturkenboom, PhD*‡; Alfredo Nicolosi, PhD§࿣; Luigi Cantarutti, MD¶; Salvatore Mannino, MD#; Gino Picelli‡; Antonio Scamarcia¶; and Carlo Giaquinto, MD**, for the NSAIDs Paediatric Research Group ABSTRACT. Background and Objective. Results from Participants. Children aged 0 to 14 years and regis- a relatively small case-control study recently showed that tered with 1 of the collaborating pediatricians between niflumic acid increases the risk of serious mucocutane- January 1, 1998, and May 31, 2001. ous reactions in children. As a consequence, the Italian Main Outcome Measures. The incidence rate of se- Ministry of Health sent a “Dear Doctor” letter in June vere (hospitalized or referred) and mild mucocutaneous 2001 to warn pediatricians about the alleged adverse reactions (exanthema, disseminated or localized pruritus, effects. The objective of this study was to estimate and urticaria, angioedema, fixed eruption, dermatitis, ery- compare the incidence of mild and severe mucocutane- thema multiforme, vesicles, bullae, pustules, toxic epi- ous reactions among children using niflumic acid, other dermal necrolysis, purpura, and vasculitis) was estimated nonsteroidal antiinflammatory drugs (NSAIDs), or non- during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following opioid analgesics. covariates were assessed: age, gender, region, year, indi-
    [Show full text]
  • Nonsteroidal Anti-Inflammatory Drugs in Cats: a Review
    Veterinary Anaesthesia and Analgesia, 2007, 34, 228–250 doi:10.1111/j.1467-2995.2006.00322.x REVIEW Nonsteroidal anti-inflammatory drugs in cats: a review B Duncan X Lascelles* BVSc, PhD, Diplomate ACVS and ECVS, Michael H Court BVSc, PhD, Diplomate ACVA, Elizabeth M Hardie* DVM, PhD, Diplomate ACVS & Sheilah A Robertsonà BVMS, PhD, Diplomate ACVA and ECVA *Comparative Pain Research Laboratory, Department of Clinical Sciences, North Carolina State University, Raleigh, NC, USA Comparative and Molecular Pharmacogenetics Laboratory, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA àDepartment of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA Correspondence: BDX Lascelles, Comparative Pain Research Laboratory, Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27606, USA. E-mail: [email protected] The acceptance of NSAIDs in small animal Abstract practice increased dramatically in the 1990s, with Objective To review the evidence regarding the use the realization that they could play an important of nonsteroidal anti-inflammatory drugs (NSAIDs) role in the management of perioperative pain (Reid in cats & Nolan 1991; Nolan & Reid 1993; Lascelles et al. 1994), and with the introduction of several new Databases used PubMed, CAB abstracts. NSAIDs. Currently, several NSAIDs (aspirin, car- profen, cinchophen, deracoxib, etodolac, firocoxib, Conclusions Nonsteroidal anti-inflammatory drugs flunixin, ketoprofen, meloxicam, phenylbutazone, should be used with caution in cats because of tepoxalin, tolfenamic acid and vedaprofen) have their low capacity for hepatic glucuronidation, approval for the control of canine perioperative and/ which is the major mechanism of metabolism and or chronic pain in various countries.
    [Show full text]
  • Inhibitory Effects of Anti-Inflammatory Drugs on Interleukin-6 Bioactivity
    June 2001 Notes Biol. Pharm. Bull. 24(6) 701—703 (2001) 701 Inhibitory Effects of Anti-Inflammatory Drugs on Interleukin-6 Bioactivity a a a a b Bo-Seong KANG, Eun-Yong CHUNG, Yeo-Pyo YUN, Myung Koo LEE, Yong Rok LEE, c a ,a Ki-Sung LEE, Kyung Rak MIN, and Youngsoo KIM* College of Pharmacy, Chungbuk National University,a Cheongju 361–763, Korea, College of Engineering, Yeungnam University,b Kyongsan 712–749, Korea, and Research Center for Biomedical Resources, Pai-Chai University,c Taejon 302–735, Korea. Received November 20, 2000; accepted February 14, 2001 Interleukin-6 (IL-6) is known as a proinflammatory cytokine involved in immune response, inflammation, and hematopoiesis. Inhibitory effects of anti-inflammatory drugs on IL-6 bioactivity using IL-6-dependent hy- bridoma have been evaluated. Three out of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) showed IC50 val- 5 . ues of less than 100 mM, which were in the order of oxyphenylbutazone hydrate (IC50 7.5 mM) meclofenamic acid sodium salt (31.9 mM).sulindac (74.9 mM). Steroidal anti-inflammatory drugs (SAIDs) exhibited significant inhibitory effects at 100 mM on the IL-6 bioactivity, and their inhibitory potencies were in the order of budesonide 5 . (IC50 2.2 mM) hydrocortisone 21-hemisuccinate (6.7 mM), prednisolone (7.5 mM), betamethasone (10.9 mM) dex- amethasone (18.9 mM) and triamcinolone acetonide (24.1 mM). The results would provide an additional mecha- nism by which anti-inflammatory drugs display their anti-inflammatory and immunosuppressive effects at higher concentrations. Key words anti-inflammatory drugs; IL-6 inhibitor; oxyphenylbutazone hydrate; budesonide Interleukin-6 (IL-6) is a proinflammatory cytokine which were purchased from GIBCO BRL Products (Gaithersburg, is produced by both lymphoid and nonlymphoid cells.1) The MD, U.S.A.) and rhIL-6 from Wako Pure Chemical Ind., Ltd.
    [Show full text]