Fatal Hepatitis Associated with Diclofenac
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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. -
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 -
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. -
Cross-Reactive Mechanism for the False Elevation of Free Triiodothyronine in the Patients Treated with Diclofenac
Endocrine Journal 2001, 48 (6), 717-722 NOTE Cross-Reactive Mechanism for the False Elevation of Free Triiodothyronine in the Patients Treated with Diclofenac KEIZO KASONO, HAJIME HIKINO*, SHINJI FUJINO**, NoBUYUKI TAKEMOTO*, TosHIHIRO KAI*, KIYosHI YAMAGUCHI***, FUMio KONISHI* AND MASANOBU KAWAKAMI Department of Endocrinology and Metabolism, Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan *Department of Surgery , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan **Department of Pathology , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan ***Department of Neurology , Jichi Medical School, Omiya Medical Center, 1-847, Amanuma-cho, Saitama 330-8503, Japan Abstract. We report three cases of patients exhibiting a false elevation of serum free triiodothyronine (FT3) as a result of a cross-reaction with diclofenac. The first case is a 66-yr-old woman with a long history of rheumatoid arthritis (RA). The patient was receiving diclofenac for the treatment of her RA. The patient was subsequently diagnosed as having thyroid papillary adenocarcinoma and received a subtotal thyroidectomy. After the operation, the patient exhibited postoperative hypothyroidism except for a gradual elevation of FT3. The other two patients also exhibited an elevated serum FT3 level after the administration of diclofenac. Serum FT3 levels in these pa- tients decreased to normal or below normal after diclofenac administration was discontinued. In the first case, the elimination of immunoglobulin from the sera using polyethylene glycol precipitation did not reduce the FT3 level. In our hospital, Vitros ECi (enhanced chemiluminescence enzyme immunoassay) system and Vitros FT3 kit were used for FT3 assay. -
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. -
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. -
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 -
And Thin-Layer Chromatography (Drug Skreen)1)
Oeilerich, Külpmann and Haeckel: Drug screening by enzyme immunoassay and .tliin-layer chromatography 275 J. Clin. Chem. Clin. Biochem. Vol. 15, 1977, pp. 275-283 Drug Screening by Enzyme Immunoassay (EMIT) and Thin-Layer Chromatography (Drug Skreen)1) By M. Oellerich, W. R. Külpmann and/?. Haeckel Technical Assistance : F. Behrends,L hberner and K. Petry Institut für Klinische Chemie (Geschäftsführcnder Direktor: Prof. Dr. Dr. J. Büttner) Medizinische Hochschule Hannover (Received June 12/December 16, 1976) Herrn Prof. Dr. Dr. h. c. G. Schettler zum 60. Geburtstag gewidmet Summary: Urine samples (n = 300) were examined for drugs by thin-layer chromatography ("Drug Skreen", Brink- mann Corp.) and by the "Enzyme Multiplied Immunoassay Technique" ("Emit", Syva Corp.). The results of both methods were compared for the detection of opiates, barbiturates and amphetamines. In more than 90% of the determinations identical results were obtained with both methods. About 10% of the results of the Emit barbiturate assay differed from those of thin-layer chromatography and therefore had to be further investigated by gas liquid chromatography. It could be demonstrated that the barbiturate determination by the Emit system correlated better with the results of gas liquid chromatography. From the results of this study it is suggested that thin-layer chromato- graphy is used as a screening test, and to confirm positive results with other methods such as Emit. If the abuse of barbiturates or opiates is suspected the corresponding Emit test should also be performed, even in cases of a negative thin-layer Chromatograph*, -screening. Confirmation with a third method such as gas liquid chromatography is necessary, if thin-layer chromatography and Emit lead to divergent results. -
Pharmaceuticals As Environmental Contaminants
PharmaceuticalsPharmaceuticals asas EnvironmentalEnvironmental Contaminants:Contaminants: anan OverviewOverview ofof thethe ScienceScience Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Why and how do drugs contaminate the environment? What might it all mean? How do we prevent it? Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada This talk presents only a cursory overview of some of the many science issues surrounding the topic of pharmaceuticals as environmental contaminants Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada A Clarification We sometimes loosely (but incorrectly) refer to drugs, medicines, medications, or pharmaceuticals as being the substances that contaminant the environment. The actual environmental contaminants, however, are the active pharmaceutical ingredients – APIs. These terms are all often used interchangeably Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdfNational -
Søgeprotokol for Nationale Kliniske Retningslinjer
Søgeprotokol for nationale kliniske retningslinjer Projekttitel/aspekt NKR behandling af patienter med lumbal spinalstenose – Søgning efter primærlitteratur Fagkonsulent /projektleder Rikke Rousing / Maria Herlev Ahrenfeldt Søgespecialist Kirsten Birkefoss Senest opdateret 23.12.2016 Fokuserede spørgsmål Bør patienter med lumbal spinalstenose have tilbudt aktiv PICO 1: behandling i form af superviseret træning fremfor vanlig behandling? PICO 2: Bør patienter med lumbal spinalstenose have tilbudt ledmobiliserende behandling frem for vanlig behandling? PICO 3: Bør patienter med lumbal spinalstenose have tilbudt paracetamol frem for ingen smertestillende behandling? PICO 4: Bør patienter med lumbal spinalstenose have tilbudt non steroid antiinflammatorisk medicin (NSAID) frem for ingen smertestillende behandling? PICO 5: Bør patienter med lumbal spinalstenose have tilbudt smertestillende medicin i form af opioider i tillæg til eventuel behandling med svage smertestillende? PICO 6: Bør patienter med lumbal spinalstenose have tilbudt muskelrelaxantia i tillæg til eventuel behandling med svage smertestillende? PICO 7: Bør patienter med lumbaspinalstenose have tilbudt medicin for neuropatiske smerter? PICO 8: Bør patienter med lumbal spinalstenose have tilbudt kirurgisk dekompression i tilfælde af manglende effekt af ikke kirurgisk behandling? PICO 9: Bør patienter med lumbal spinalstenose have tilbudt stivgørende operation med eller uden instrumentering i tillæg til dekompression? PICO 10: Bør patienter opereret for lumbal spinalstenose tilbydes -
Variable in Their Efficacy? a Description of Ion Trapping
Annals of the Rheumatic Diseases 1993; 52: 241-243 241 HYPOTHESIS Why are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping G A Ellis, D R Blake Hypothesis Non-steroidal anti-inflammatory drugs vary in Our hypothesis is that acidic non-steroidal their aqueous solubility, but most are highly anti-inflammatory drugs (NSAIDs) undergo albumin bound and will be co-distributed with ion trapping in acidotic tissue and that this this protein. Diffusion of an NSAID into the affects not only their gastrotoxicity, which is cell follows Fick's law, as it is dependent on the well known, but also their selectivity for, and concentration gradient across the plasma their efficacy in, inflammatory joint disease. membrane and the lipid/water partition Tissue acidosis may not be a feature of all coefficient of the drug molecule. chronic inflammatory disease states, but it does For weak acids, such as most NSAIDs, the occur in inflammatory joint disease and is effective concentration gradient is that of the highly variable depending on the extent of the non-ionised form, as ionised molecules are not mismatch between synovial perfusion and lipid soluble metabolic demand. This mismatch is influ- HD D- + H+ enced not only by disease activity, but also by Non-ionised Ionised joint movement, which causes transient hypoxic episodes. Interventions, such as rest The position ofthe equilibrium depends on the and drug treatment, would serve to reduce ion intrinsic ionisation constant of the molecule trapping and, therefore, NSAID efficacy (pKa) and on the pH value of the aqueous through their effects on disease activity. -
Non-Steroidal Anti-Inflammatory Drugs B.L
Br. J. clin. Pharmac. (1983), 16, 633-638 A METHOD FOR PREDICTING THE PHOTOTOXICITY OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS B.L. DIFFEY1 & S. BROWN2 Departments of Medical Physics' and Pharmacy2, Dryburn Hospital, Durham, DH1 5TW 1 The photosensitisation potential of several non-steroidal anti-inflammatory drugs (NSAIDs) has been investigated in vivo using an irradiation monochromator. 2 Evidence ofabnormal, immediate photosensitivity was obtained in 13 of the 38 patients taking one of four out of seven different NSAIDs. 3 A simple mathematical model was developed to predict the likelihood of photosensitivity occurring with a given drug by considering the mass of drug normally ingested, the spectral absorption characteristics of the drug, and the quantity and spectral quality of the radiation (e.g. sunlight) to which the patient may be exposed. Keywords phototoxicity non-steroidal anti-inflammatory drugs Introduction The non-steroidal anti-inflammatory drugs (NSAIDs) differences in skin pigmentation reflecting variations have gained prominence in recent years as useful in the penetration of light into the skin. therapeutic agents in the management of rheumatoid The NSAIDs, although chemically distinct, share and osteoarthritis. However several of these drugs many common properties. The exact mode of action have been reported as inducing adverse cutaneous of each drug is not fully understood, but all these photosensitive reactions (Committee on Safety of drugs are potent inhibitors of the enzyme prosta- Medicines, personal communication). The photo- glandin synthetase (Simon & Mills, 1980). This sensitisation potential of many of these drugs, parti- property undoubtedly plays an important part in the cularly benoxaprofen, has subsequently been con- anti-inflammatory effect, but there is no clearly de- firmed by laboratory investigation (Wiskemann, 1981; fined relationship between the inhibitory potency of a Kligman & Kaidbey, 1982; Ferguson et al., 1982; drug against prostaglandin synthetase in vitro and Diffey & Daymond, 1983; Diffey etal., 1983).