DOCSLIB.ORG

A Comparison of the Ocular Anti-Inflammatory Activity of Steroidal and Nonsteroidal Compounds in the Rat

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Comparison of the Ocular Anti-Inflammatory Activity of Steroidal and Nonsteroidal Compounds in the Rat No. 8 Reporrs 1143 sheets. The cells retain their epithelial morphology nea and iris-ciliary body of the rabbit. Invest Ophthalmol Vis and synthesize cAMP in response to /3-adrenergic but Sci 17:1069, 1978. 4. Klyce SD, Palkama KA, Harkonen M, Marshall WS, Huht- not serotonergic stimulation. aniity S, Mann KP, and Neufeld AH: Neural serotonin stim- Key words: epithelium, cornea, rabbit, cell culture, /3-ad- ulates chloride transport in the rabbit corneal epithelium. In- renergic response, growth factors, cholera toxin, cAMP, vest Ophthalmol Vis Sci 23:181, 1982. serotonergic response 5. Neufeld AH, Ledgard SE, Jumblatt MM, and Klyce SD: Se- rotonin-stimulated cyclic AMP synthesis in the rabbit corneal Acknowledgments: The authors thank Sally Ledgard for epithelium. Invest Ophthalmol Vis Sci 23:193, 1982. technical assistance and Yasuo Ishii for electron micros- 6. Lowry OH, Rosebrough NJ, Farr AL and Randall RJ: Protein copy. measurement with the Folin phenol reagent. J Biol Chem 193:265, 1951. From the Eye Research Institute of Retina Foundation and 7. Gipson IK and Grill SM: A technique for obtaining sheets of Department of Ophthalmology, Harvard Medical School, Boston, intact rabbit corneal epithelium. Invest Ophthalmol Vis Sci Massachusetts. Supported in part by USPHS grants EY-02360 and 23:269, 1982. EY-02367. Submitted for publication: July 27, 1982. Reprint re- 8. Barnes D and Sato G: Methods for growth of cultured cells quests: Marcia M. Jumblatt, Eye Research Institute of Retina in serum-free medium. Anal Biochem 102:255, 1980. Foundation, 20 Staniford Street, Boston, MA 02114. 9. Taylor-Papadimitriou J, Purkis P, and Fentiman IS: Cholera toxin and analogues of cyclic AMP stimulate the growth of References cultured human mammary epithelial cells. J Cell Physiol 102:317, 1980. 1. Sundar-Raj CV, Freeman IL, and Brown SI: Selective growth 10. Green H: Cyclic AMP in relation to proliferation of the epi- of rabbit corneal epithelial cells in culture and basement mem- dermal cell: a new view. Cell 15:801, 1978. brane collagen synthesis. Invest Ophthalmol Vis Sci 19:1222, 11. Jumblatt MM and Neufeld AH: Characterization of cyclic 1980. AMP mediated wound closure of the rabbit corneal epithe- 2. Sun TT and Green H: Cultured epithelial cells of cornea, con- lium. Curr Eye Res 1:189, 1981. junctiva and skin: Absence of marked intrinsic divergence of 12. Jumblatt MM, Fogle JA, and Neufeld AH: Cholera toxin stim- their differentiated states. Nature 269:489, 1977. ulates adenosine 3',5'-monophosphate synthesis and epithelial 3. Neufeld AH, Zawistowski KA, Page ED, and Bromberg BB: wound closure in the rabbit cornea. Invest Ophthalmol Vis Influences on the density of/8-adrenergic receptors in the cor- Sci 19:1321, 1980. A Comparison of the Ocular Anti-inflammatory Activity of Steroidal and Nonsteroidal Compounds in the Rat P. Dharrocherjee, R. N. Williams, and K. E. Eakins The anti-inflammatory activities of steroidal and nonste- factorily for comparative evaluation of anti-inflammatory roidal compounds have been evaluated in the rat model of agents. Invest Ophthalmol Vis Sci 24:1143-1146, 1983 ocular inflammation induced by subcutaneous injection of lipopolysaccharides. Dexamethasone sodium phosphate, BW755C, flurbiprofen, indomethacin, and benoxaprofen The anti-inflammatory drugs such as aspirin and were administered orally or topically for 24 or 48 hrs. Oral indomethacin, inhibit the enzyme, cyclo-oxygenase, administration of dexamethasone, BW755C, and flurbipro- which converts arachidonic acid into prostaglandins.' fen inhibited iris-vasodilatation and leukocyte accumulation Unlike the aspirin-like drugs, the anti-inflammatory in the anterior chamber in a dose-dependent manner. In- corticosteroids reduce the formation of both cyclo- domethacin and benoxaprofen were active only at high oxygenase and lipoxygenase products of arachidonate doses. Topical administration of these compounds inhibited metabolism by preventing the release of the precursor the inflammatory responses in a similar manner. The in- acid, arachidonic acid.2'3 This additional inhibition hibitory effect on leukocyte accumulation by these com- of leukotriene formation might be responsible for the pounds was greater than their effect on vasodilatation. wider profile of anti-inflammatory activity exhibited BW755C, a phenyl pyrazoline derivative, which is an in- hibitor of both the cyclooxygenase and lipoxygenase path- by the corticosteroids. ways of arachidonic acid metabolism was the most active Although effective clinically as anti-inflammatory nonsteroidal compound and had an anti-inflammatory pro- agents, corticosteroids have a large number of un- file similar to dexamethasone. The results of this study also, desirable side-effects when used either systemically or indicate that the model of rat ocular inflammation induced topically. A compound having the ability of a corti- by subcutaneous injection of endotoxin can be used satis- costeroid to prevent the formation of the products of 0146-0404/83/0800/1143/$ 1.00 © Association for Research in Vision and Ophthalmology Downloaded from iovs.arvojournals.org on 09/29/2021 1144 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / Augusr 1983 Vol. 24 JL ment of the treatments. Dilatation of iris blood vessels 100 JL 1 JL was assessed, and the severity was scored (0 for nor- mal, 1 as mild, 2 moderate, and 3 as^severe). At the JL JL 1 end of the experimental period, animals were killed Ji with sodium pentobarbitone, the anterior chamber 50 Ji 1 T punctured, and the aqueous humor collected in a " ft disposable graduated capillary tube and mixed with • 0.1 ml heparinized saline. Leukocytes were counted in a single blind manner in a Neubauer Chamber. To 1 1 compare the activity of various compounds and to 1 T analyse the data statistically, each value of the va- 100 T i 1 sodilation score and leukocyte count was converted to the percent of the mean of the control. The mean Jl Jl of these values were then compared statistically with Ti Jl Jl Jl JL that of the control using unpaired t-test for groups 50 Jl J, consisting of unequal number of observations. J- Preparation of drug solutions. Dexamethasone So- 5 dium phosphate and BW755C were dissolved in sa- 5 3 q q q in q q .2 o in .0 8 .12 o o in o o* o o in CM in in in o CM line immediately prior to administration. Indometh- _ o 6 o *- rsi Dexamethasone BW755C Flurbiprolen Indomethacin Benoxaprofen acin, flurbiprofen and benoxaprofen were dissolved mg/kg mg/kg mg/kg mg/kg mg/kg in saline with the aid of equimolar concentration of Fig. 1. The inhibitory activity of the anti-inflammatory agents sodium carbonate yielding clear solutions with pH administered orally three times in 24 hrs on the iris-vasodilatation and leukocyte accumulation in the aqueous humor. Each column between 7.0 and 7.5. expressed as the percent of control values is the mean of 16-20 Oxyphenbutazone being insoluble in water was so- eyes. The figures within the columns are the doses and the bars lubilised in polysorbate mono-oleate and then diluted represent ±SEM. *P < 0.05. with phosphate buffer, pH 7.5 to a final concentration of 5% polysorbate mono-oleate. both pathways of arachidonic acid metabolism but Results. The anti-inflammatory effects of the test free of their undesirable side-effects, would be valu- compounds following oral administration on the re- able as a topical ocular anti-inflammatory drug. The sponses of the eye to endotoxin are summarized in nonsteroidal anti-inflammatory compound BW755C Figure 1. Dexamethasone effectively inhibited both (3-amino-1 -(3 trifluromethylphenyl)-2-pyrazoline) the vasodilation and leukocyte accumulation in a may be representative of such a class of drugs, since dose-dependent manner. Both the phenyl pyrazoline it is equi-active in inhibiting cyclo-oxygenase and li- derivative, BW755C, and flurbiprofen exhibited sim- poxygenase activity, and possesses a wider profile of ilar anti-inflammatory activity but were both less po- anti-inflammatory activity than the aspirin-like drugs.4 tent than dexamethasone. Benoxaprofen and indo- In the present study, we have compared the anti- methacin at 20 mg/kg and 10 mg/kg respectively re- inflammatory activity of the aspirin-like drugs, flur- duced leukocyte accumulation by about 40% without biprofen, indomethacin and benoxaprofen, with a significant modification of the initial vasodilation. corticosteroid, dexamethazone, and BW755C, fol- This inhibition was maximal for both compounds lowing both oral and topical administration using the since higher concentrations did not result in any fur- newly described rat model of ocular inflammation.56 ther reduction in leukocyte accumulation. Materials and Methods. Ocular inflammation in The effects of topical administration of these com- the rat was induced by injecting Shigella endotoxin pounds for a period of 24 hrs are seen in Figure 2. into the foot pad as described by Bhattacherjee, Wil- With the exception of dexamethasone, none of the liams, and Eakins.6 Immediately after the injection, compounds significantly altered either the vasodila- groups of 8-10 rats were treated with the anti-inflam- tion or the leukocyte accumulation at this period of matory compounds either orally three times a day for treatment. Dexamethasone on the other hand was 24 hrs or topically three times a day either for 24 or highly effective on both parameters of inflammation 48 hrs. A constant volume of 10 n\ and 500 n\ was following 24 hrs of treatment. used respectively for topical and oral administration. However, the anti-inflammatory activity of some At each dose level, a control group treated with ve- but not all, of these compounds became apparent hicle alone was always included. when the period of treatment was extended to 48 hrs Animals were then examined under a slit lamp 24 (Fig. 3). For example, both BW755C and flurbipro- and 48 hrs after endotoxin injection and commence- fen, which were without a significant inhibitory action Downloaded from iovs.arvojournals.org on 09/29/2021 No.
Load more

Recommended publications
  • United States Patent (19) 11 Patent Number: 5,955,504 Wechter Et Al
    USOO5955504A United States Patent (19) 11 Patent Number: 5,955,504 Wechter et al. (45) Date of Patent: Sep. 21, 1999 54 COLORECTAL CHEMOPROTECTIVE Marnett, “Aspirin and the Potential Role of Prostaglandins COMPOSITION AND METHOD OF in Colon Cancer, Cancer Research, 1992; 52:5575–89. PREVENTING COLORECTAL CANCER Welberg et al., “Proliferation Rate of Colonic Mucosa in Normal Subjects and Patients with Colonic Neoplasms: A 75 Inventors: William J. Wechter; John D. Refined Immunohistochemical Method.” J. Clin Pathol, McCracken, both of Redlands, Calif. 1990; 43:453-456. Thun et al., “Aspirin Use and Reduced Risk of Fatal Colon 73 Assignee: Loma Linda University Medical Cancer." N Engl J Med 1991; 325:1593-6. Center, Loma Linda, Calif. Peleg, et al., “Aspirin and Nonsteroidal Anti-inflammatory Drug Use and the Risk of Subsequent Colorectal Cancer.” 21 Appl. No.: 08/402,797 Arch Intern Med. 1994, 154:394–399. 22 Filed: Mar 13, 1995 Gridley, et al., “Incidence of Cancer among Patients With Rheumatoid Arthritis J. Natl Cancer Inst 1993 85:307-311. 51) Int. Cl. .......................... A61K 31/19; A61K 31/40; Labayle, et al., “Sulindac Causes Regression Of Rectal A61K 31/42 Polyps. In Familial Adenomatous Polyposis” Gastroenterol 52 U.S. Cl. .......................... 514/568; 514/569; 514/428; ogy 1991 101:635-639. 514/416; 514/375 Rigau, et al., “Effects Of Long-Term Sulindac Therapy On 58 Field of Search ..................................... 514/568, 570, Colonic Polyposis” Annals of Internal Medicine 1991 514/569, 428, 416, 375 11.5:952-954. Giardiello.et al., “Treatment Of Colonic and Rectal 56) References Cited Adenomas With Sulindac In Familial Adenomatous Poly U.S.
    [Show full text]
  • Comparative Study of the Efficacy of Flunixin, Ketoprofen and Phenylbutazone in Delman Horses with Mild Colic
    Sys Rev Pharm 2020; 11(5): 464 468 A multifaceted review journal in the field of pharmacy E-ISSN 0976-2779 P-ISSN 0975-8453 Comparative Study of the Efficacy of Flunixin, Ketoprofen and Phenylbutazone in Delman Horses with Mild Colic Agus Purnomo1, Arya Pradana Wicaksono2, Dodit Hendrawan2, Muhammad Thohawi Elziyad Purnama3* 1Department of Veterinary Surgery and Radiology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, DI Yogyakarta, 55281, Indonesia 2Postgraduate Studies, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, 60115, Indonesia 3Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, 60115, Indonesia *Corresponding author E-mail: [email protected] Article History: Submitted: 26.02.2020 Revised: 16.04.2020 Accepted: 21.05.2020 ABSTRACT This study aimed to evaluate the efficacy of flunixin, ketoprofen and multiple range test. The results showed a significant alleviation in all phenylbutazone on serum biochemistry, plasma catecholamines and observed variables on Day 13, although the use of various NSAIDs serum cortisol in Delman horses with mild colic. During the study showed no significant difference. period, 32 horses were evaluated due to mild colic. Flunixin, Keywords: serum biochemical, catecholamine, cortisol, colic, NSAIDs ketoprofen, and phenylbutazone were administered intravenously at Correspondence: the recommended dose rates of 1.0; 2.2 and 4.4 mg/kg, respectively. Muhammad Thohawi Elziyad Purnama Administration of the NSAIDs commenced on Day 1 and continued Department of Veterinary Anatomy, Faculty of Veterinary Medicine, every 12 h for 12 days. Blood samples collected between days 2, 5, 9 Universitas Airlangga, Surabaya, 60115, Indonesia and 13 to evaluate AST, ALP, GGT, creatinine, urea, epinephrine, E-mail: [email protected] norepinephrine, and cortisol level.
    [Show full text]
  • Non-Steroidal Anti-Inflammatory Drugs (Nsaids)
    NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ANALYSIS IN MILK BY QUECHERS AND LC-MS: LOW AND HIGH RESOLUTION DETECTION AND CONFIRMATION APPROACHES A. Rúbies1, L. Guo2, I. Beguiristain1, F. Centrich1, M. Granados2 1. Laboratori Agència de Salut Pública de Barcelona, 2. Departament de Química Analítica - Universitat de Barcelona. * INTRODUCTION NON-STEROIDAL ANTI-INFLAMATORY DRUGS (NSAIDs) Non-steroidal anti-inflammatory drugs (NSAIDs) are used as anti-inflammatory, analgesic and OXICAMS ANTHRANILIC ACID DERIVATIVES ACETIC ACID antipyretic drugs in medicine and veterinary. Their action mechanism is based on the blocking of PROPIONIC ACID DERIVATIVES DERIVATIVES the biosynthesis of prostaglandins. NSAIDs are highly effective and extensively used, but they have some adverse side effects, such as hepatotoxicity, renal disorders or allergic reactions. In the European Union, to assure food safety and protect consumers, maximum residue limits have been established for some authorised NSAIDs in food products. Therefore, high throughput and reliable analytical methodology is required for the effective control of NSAIDs in food from animal Flufenamic acid origin. Liquid chromatography (LC) coupled to mass spectrometry (MS) is currently the technique of choice in confirmatory analysis of NSAIDs residues. We present a new method for the determination of representative NSAIDs in milk based on QuEChERS methodology, LC-MS/MS and UHPLC-HRMS. Meloxicam Ketoprofen Diclofenac EU Maximum Residue Limits (MRLs) Recommended NSAIDs concentrations for NSAIDs in milk.
    [Show full text]
  • Fatal Hepatitis Associated with Diclofenac
    Gut: first published as 10.1136/gut.27.11.1390 on 1 November 1986. Downloaded from Gut, 1986, 27, 1390-1393 Case reports Fatal hepatitis associated with diclofenac E G BREEN, J McNICHOLL, E COSGROVE, J MCCABE, AND F M STEVENS From the Department of Medicine, Regional Hospital, Galway, Eire SUMMARY Non-steroidal anti-inflammatory agents (NSAIDS) are a well recognised cause of hepatotoxicity. Diclofenac, a relatively new NSAID, was first introduced into the UK in 1979. Five cases of hepatitis have recently been reported, principally in the French literature. -5 We report the first fulminant case of hepatitis in the English literature in a patient taking diclofenac and indomethacin. Diclofenac is a member of the arylalkanoic group of 100 mg per day for five weeks. Ferrous sulphate one NSAIDS (Fig. 1). Three other agents in this group tablet daily was added on 16 May. The patient was have been shown to be significantly hepatotoxic. admitted to hospital on 26 June. A week before this Ibufenac was withdrawn from circulation because of he had felt unwell with anorexia, nausea, abdominal the frequent rise in transaminases,6 7 the use of discomfort, and dark urine. On admission he was benoxaprofen was stopped in Britain after 10 icteric, the liver edge was palpable 4 cm below the patients died with hepatitis8 9 and more recently a costal margin and there were no signs of chronic fatal case of hepatitis due to pirprofen has been liver disease. Ultrasound showed early ascites with reported."' Early reports about diclofenac showed no obstruction of the biliary tract.
    [Show full text]
  • In 1977 a Conclusion of the National Association of State Racing Commissioners Veterinary-Chemist Advisory Board Concluded That
    Lawrence R. Soma, VMD, University of Pennsylvania, School of Veterinary Medicine. This review was undertaken at the request of the Racing Medication and Testing Consortium, Medication Advisory Committee. Review: The use of phenylbutazone in the horse This review presents a brief historical prospective of the genesis of regulated medication in the US racing industry of which the non-steroidal anti-inflammatory drug phenylbutazone (PBZ) is the focus. It presents some historical guide posts in the development of the current rules on the use on PBZ by racing jurisdictions in the US. Based on its prevalent use, PBZ still remains a focus of attention. The review examines the information presented in a number of different models used to determine the effects and duration of PBZ in the horse. They include naturally occurring lameness and reversible induced lameness models that directly examine the effects and duration of the administration of various doses of PBZ. The review also examines indirect plasma and tissue models studying the suppression of the release of arachidonic acid- derived mediators of inflammation. The majority of studies suggest an effect of PBZ at 24 hours at 4.4 mg/kg. This reflects and substantiates the opinion of many clinical veterinarians, many of whom will not perform a pre-purchase lameness examination unless the horse is shown to be free of NSAID. This remains the opinion of many Commission Veterinarians in that they wish to examine a horse pre-race without the possibility of a NSAID interfering with the examination and masking possible musculoskeletal conditions. Based on scientific studies, residual effects of PBZ remain at 24 hours following administration.
    [Show full text]
  • Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Final, July 2009
    Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 51, rm. 2201 Silver Spring, MD 20993-0002 Tel: 301-796-3400; Fax: 301-847-8714; E-mail: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach, and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 Tel: 800-835-4709 or 301-827-1800 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND: DILI ................................................................................................... 2 III. SIGNALS OF DILI AND HY’S
    [Show full text]
  • Benoxaprofen Irony Is Inescapable That While Manuscripts
    BRITISH MEDICAL JOURNAL VOLUME 285 18 SEPTEMBER 1982 809 Br Med J (Clin Res Ed): first published as 10.1136/bmj.285.6344.809-a on 18 September 1982. Downloaded from favourable groups of alcoholics (such as single, trials and post-marketing surveillance pro- the carefully controlled and monitored clinical divorced, or widowed men and women) is as grammes, often undergo extensive revision trial. Unless there is prompt reporting of the yet unknown but may appear doubtful to the before acceptance for publication, paid results of such trials by the sponsoring drug practising clinician.3 The statement that, advertisements extolling only the virtues of company to all governmental agencies in "Treatment may actually make some alco- various products generally are accepted countries marketing or planning to market a holics worse" by protecting them from the without modification. particular drug, the Committee on Safety of consequences of their drinking or by fostering In the face of the need to maintain fiscal Medicines, the Food and Drug Administration, inactivity surely applies only to utterly inade- viability while upholding the highest editorial and similar agencies in other countries will quate "treatment." The risks arising from the standards, what is a medical journal to do in not be acting on the best available information. behaviour of well-meaning "enablers" who regard to advertising? The issue needs to be shelter the alcoholic from experiencing the explored by both editors and medical associa- SIDNEY M WOLFE painful effects of his drinking on himself (and tions at their meetings. One proposal has been EVE BARGMANN others) and the importance of fostering the raised' and seconded2 for a "physician Health Research Group, patient's responsibility for his recovery, his boycott" of drugs that are unethically pro- Washington DC 20036 own initiative, and active participation in the moted.
    [Show full text]
  • Benoxaprofen
    BRITISH LONDON, SATURDAY 14 AUGUST 1982 Br Med J (Clin Res Ed): first published as 10.1136/bmj.285.6340.459 on 14 August 1982. Downloaded from MEDICAL^s JOURNAL Benoxaprofen Two years after benoxaprofen (Opren) was launched in a The mode of action of benoxaprofen appears to differ blaze of publicity the Committee on Safety of Medicines has from that of other non-steroidal anti-inflammatory agents. It suspended its product licence on the grounds of concern acts directly on mononuclear cells, inhibiting their chemotactic about serious side effects (see p 519). The public has been response; it inhibits the lipoxygenase enzyme; and it has a alarmed by the total of 61 deaths in patients, mostly elderly, mild inhibitory action on the formation of other prosta- taking benoxaprofen and by the admission of the Committee glandins.'8 19 This combination of properties is of great on Safety of Medicines that it has received 3500 reports of theoretical interest, since nearly all other non-steroidal adverse reactions. Has the Committee on Safety of Medicines anti-inflammatory drugs appear to act by inhibiting prosta- acted too slowly on this occasion ? What are the- lessons to be glandin synthetase. There is some preliminary evidence that learnt ? benoxaprofen may have disease-modifying properties in Firstly, the benoxaprofen affair shows the dangers of current rheumatoid arthritis.20 marketing policies by some pharmaceutical companies. After A drug with unusual properties may be expected to have its clinical trials the drug was put on to the market with massive unusual side effects-and both the frequency and nature of publicity on radio and in newspapers encouraging patients to these effects have been surprising.
    [Show full text]
  • An in Vitro Approach to Detect Metabolite Toxicity Due to CYP3A4
    Toxicology 216 (2005) 154–167 An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics Luisella Vignati ∗, Elisa Turlizzi 1, Sonia Monaci, Pietro Grossi, Ruben de Kanter, Mario Monshouwer 2 Department of Pre-Clinical Development, Nerviano Medical Sciences S.r.l., V.le Pasteur, 10, 20014, Nerviano, MI, Italy Received 22 June 2005; received in revised form 3 August 2005; accepted 3 August 2005 Available online 19 September 2005 Abstract Many adverse drug reactions are caused by the cytochrome P450 (CYP) dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-mediated toxicity and to improve safety of drug candidates, we developed two in vitro cell-based assays by combining an activating system (human CYP3A4) with target cells (HepG2 cells): in the first method we incubated microsomes containing cDNA-expressed CYP3A4 together with HepG2 cells; in the second approach HepG2 cells were transiently transfected with CYP3A4. In both assay systems, CYP3A4 catalyzed metabolism was found to be comparable to the high levels reported in hepatocytes. Both assay systems were used to study ten CYP3A4 substrates known for their potential to form metabolites that exhibit higher toxicity than the parent compounds. Several endpoints of toxicity were evaluated, and the measurement of MTT reduction and intracellular ATP levels were selected to assess cell viability. Results demonstrated that both assay systems are capable to metabolize the test compounds leading to increased toxicity, compared to their respective control systems. The co-incubation with the CYP3A4 inhibitor ketoconazole confirmed that the formation of reactive metabolites was CYP3A4 dependent.
    [Show full text]
  • Reviewer Guidance
    Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2005 Good Review Practices Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) February 2005 Good Review Practices TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. GENERAL GUIDANCE ON THE CLINICAL SAFETY REVIEW .......................... 2 A. Introduction....................................................................................................................................2 B. Explanation of Terms ....................................................................................................................3 C. Overview of the Safety Review .....................................................................................................4 D. Differences in Approach to Safety and Effectiveness Data ........................................................4
    [Show full text]
  • Changes Highlighted Final Version Date of Issue: 23Rd December 2015
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2016 Section A Changed Classes/Guidelines: Changes Highlighted Final Version Date of issue: 23rd December 2015 1 A2B ANTIULCERANTS R1997r2 016 Combinations of specific antiulcerants with anti-infectives against Helicobacter pylori are classified according to the anti-ulcerant substance. For example, proton pump inhibitors in combination with these anti-infectives are classified in A2B2. A2B1 H2 antagonists R2002 Includes, for example, cimetidine, famotidine, nizatidine, ranitidine, roxatidine. Combinations of low dose H2 antagonists with antacids are classified with antacids in A2A6. A2B2 Acid Proton pump inhibitors R2003r2 016 Includes esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. A2B3 Prostaglandin antiulcerants Includes misoprostol, enprostil. A2B4 Bismuth antiulcerants Includes combinations with antacids. A2B9 All other antiulcerants R2002r2 016 Includes all other products specifically stated to be antiulcerants even when containing antispasmodics (see A3). Combinations of low dose H2 antagonists with antacids are classified with antacids in A2A6. Included are, eg carbenoxolone, gefarnate, pirenzepine, proglumide, sucralfate and sofalcone. Herbal combinations are classified in A2C. In Japan, Korea and Taiwan only, sulpiride and other psycholeptics indicated for ulcer use are also included in this group, whilst in all other countries, these compounds are classified in N5A9. Products containing rebamipide for gastric mucosal protection are classified here. Products containing rebamipide and indicated for dry eye are classified in S1K9. A2C OTHER STOMACH DISORDER PREPARATIONS R1994 Includes herbal preparations and also plain alginic acid. Combinations of antacids with alginic acid are in A2A1. 2 A4 ANTIEMETICS AND ANTINAUSEANTS A4A ANTIEMETICS AND ANTINAUSEANTS R1996 Products indicated for vertigo and Meniere's disease are classified in N7C. Gastroprokinetics are classified in A3F.
    [Show full text]
  • Non Steroidal Anti-Inflammatory Drugs
    Non Steroidal Anti‐inflammatory Drugs (NSAIDs) 4 signs of inflammation • Redness ‐ due to local vessel dilatation • Heat ‐ due to local vessel dilatation • Swelling – due to influx of plasma proteins and phagocytic cells into the tissue spaces • Pain – due to local release of enzymes and increased tissue pressure NSAIDs • Cause relief of pain ‐. analgesic • Suppress the signs and symptoms of inflammation. • Exert antipyretic action. • Useful in pain related to inflammation. Esp for superficial/integumental pain . Classification of NSAIDs • Salicylates: aspirin, Sodium salicylate & diflunisal. • Propionic acid derivatives: ibuprofen, ketoprofen, naproxen. • Aryl acetic acid derivatives: diclofenac, ketorolac • Indole derivatives: indomethacin, sulindac • Alkanones: Nabumetone. • Oxicams: piroxicam, tenoxicam Classification of NSAIDs ….. • Anthranilic acid derivatives (fenamates): mefenamic acid and flufenamic acid. • Pyrazolone derivatives: phenylbutazone, oxyphenbutazone, azapropazone (apazone) & dipyrone (novalgine). • Aniline derivatives (analgesic only): paracetamol. Clinical Classif. • Non selective Irreversible COX inhibitors • Non slective Reversible COX inhibitors • Preferential COX 2 inhibitors • 10‐20 fold cox 2 selective • meloxicam, etodolac, nabumetone • Selective COX 2 inhibitors • > 50 fold COX ‐2 selective • Celecoxib, Etoricoxib, Rofecoxib, Valdecoxib • COX 3 Inhibitor? PCM Cyclooxygenase‐1 (COX‐1): -constitutively expressed in wide variety of cells all over the body. -"housekeeping enzyme" -ex. gastric cytoprotection, hemostasis Cyclooxygenase‐2 (COX‐2): -inducible enzyme -dramatically up-regulated during inflammation (10-18X) -constitutive : maintains renal blood flow and renal electrolyte homeostasis Salicylates Acetyl salicylic acid (aspirin). Kinetics: • Well absorbed from the stomach, more from upper small intestine. • Distributed all over the body, 50‐80% bound to plasma protein (albumin). • Metabolized to acetic acid and salicylates (active metabolite). • Salicylate is conjugated with glucuronic acid and glycine. • Excreted by the kidney.
    [Show full text]