| 词条 | Diflunisal |
| 释义 |
| verifiedrevid = 460785966 | IUPAC_name = 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid | image = Diflunisal structure.svg | image2 = Diflunasil-3D-balls.png | width = 180 | width2 = 187 | tradename = | Drugs.com = {{drugs.com|monograph|diflunisal}} | MedlinePlus = a684037 | pregnancy_AU = C | pregnancy_US = C | legal_AU = S4 | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral | bioavailability = 80-90% | protein_bound = >99% | metabolism = Hepatic | elimination_half-life = 8 to 12 hours | excretion = Renal | IUPHAR_ligand = 7162 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 22494-42-4 | ATC_prefix = N02 | ATC_suffix = BA11 | PubChem = 3059 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00861 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2951 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 7C546U4DEN | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00130 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 39669 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 898 | PDB_ligand = 1FL | C=13 | H=8 | F=2 | O=3 | molecular_weight = 250.198 g/mol | smiles = O=C(O)c1cc(ccc1O)c2ccc(F)cc2F | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C13H8F2O3/c14-8-2-3-9(11(15)6-8)7-1-4-12(16)10(5-7)13(17)18/h1-6,16H,(H,17,18) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HUPFGZXOMWLGNK-UHFFFAOYSA-N }} Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin.[1] It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets. Mechanism of actionLike all NSAIDs, diflunisal acts by inhibiting the production of prostaglandins,[2] hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug.[3] It has been found to inhibit p300 and CREB-binding protein (CBP), which are epigenetic regulators that control the levels of proteins that cause inflammation or are involved in cell growth.[3] It has been reported that diflunisal has some antibacterial activity in vitro against Francisella tularensis live vaccine strain (LVS).[4] Duration of effectThough diflunisal has an onset time of 1 hour, and maximum analgesia at 2 to 3 hours, the plasma levels of diflunisal will not be steady until repeated doses are taken.[5] The long plasma half-life is a distinctive feature of diflunisal in comparison to similar drugs. To increase the rate at which the diflunisal plasma levels become steady, a loading dose is usually used. It is primarily used to treat symptoms of arthritis,[6] and for acute pain following oral surgery, especially removal of wisdom teeth.[7] Effectiveness of diflunisal is similar to other NSAIDs, but the duration of action is twelve hours or more. This means fewer doses per day are required for chronic administration. In acute use, it is popular in dentistry when a single dose after oral surgery can maintain analgesia until the patient is asleep that night. Medical uses
AmyloidosisBoth diflunisal[8][9] and several of its analogues[10] have been shown to be inhibitors of transthyretin-related hereditary amyloidosis, a disease which currently has few treatment options. Phase I trials have shown the drug to be well tolerated,[11] with a small Phase II trial (double-blind, placebo-controlled, 130 patients for 2 years) in 2013 showing a reduced rate of disease progression and preserved quality of life.[12] However a significantly larger Phase III trial would be needed to prove the drugs effectiveness for treating this condition. Side effectsGastrointestinalThe inhibition of prostaglandins has the effect of decreasing the protection given to the stomach from its own acid. Like all NSAIDS, this leads to an increased risk of stomach ulcers, and their complications, with long-term use. Elderly users of diflunisal are at greater risk for serious GI events.
Cardiovascular
Ear, nose, throat, and eye
Central nervous system
Skin
Contraindications
Cautions{{citation needed|date=June 2016}}{{div col|colwidth=22em}}
OverdoseDeaths that have occurred from diflunisal usually involved mixed drugs and or extremely high dosage. The oral {{LD50}} is 500 mg/kg. Symptoms of overdose include coma, tachycardia, stupor, and vomiting. The lowest dose without the presence of other medicines which caused death was 15 grams. Mixed with other medicines, a death at 7.5 grams has also occurred. Diflunisal usually comes in 250 or 500 mg, making it relatively hard to overdose by accident. References1. ^{{Cite journal| last1 = Adams | first1 = S. S.| title = Ibuprofen, the propionics and NSAIDs: Personal reflections over four decades| journal = Inflammopharmacology| volume = 7| issue = 3| pages = 191–197| year = 1999| pmid = 17638090| doi = 10.1007/s10787-999-0002-3}} 2. ^{{cite journal|last1=Wallace|first1=J. L.|title=Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself?|journal=Physiological Reviews|date=1 October 2008|volume=88|issue=4|pages=1547–1565|doi=10.1152/physrev.00004.2008|pmid=18923189}} 3. ^New Metabolic Pathway Reveals Aspirin-Like Compound’s Anti-Cancer Properties. June 2016 4. ^{{cite journal|last1=Jayamani|first1=E.|title=Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds|journal=Antimicrob Agents Chemother|volume=61|issue=9|doi=10.1128/AAC.00310-17|pmid=28652232|pmc=5571314|year=2017}} 5. ^1 {{cite journal |last1=Tempero|first1=KF |last2=Cirillo|first2=VJ |last3=Steelman|first3=SL |title=Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans.|journal=British Journal of Clinical Pharmacology|date=Feb 1977 |volume=4 Suppl 1|pages=31S–36S|pmid=328032|doi=10.1111/j.1365-2125.1977.tb04511.x |pmc=1428837}} 6. ^{{cite journal|last1=Brogden|first1=RN|last2=Heel|first2=RC|last3=Pakes|first3=GE|last4=Speight|first4=TM|last5=Avery|first5=GS|title=Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis.|journal=Drugs|date=Feb 1980 |volume=19|issue=2|pages=84–106|pmid=6988202|doi=10.2165/00003495-198019020-00002}} 7. ^{{cite journal|last1=Lawton|first1=GM|last2=Chapman|first2=PJ|title=Diflunisal--a long-acting non-steroidal anti-inflammatory drug. A review of its pharmacology and effectiveness in management of postoperative dental pain.|journal=Australian Dental Journal|date=Aug 1993 |volume=38|issue=4|pages=265–71|pmid=8216032|doi=10.1111/j.1834-7819.1993.tb05494.x}} 8. ^{{cite journal|last1=Tojo|first1=Kana|last2=Sekijima|first2=Yoshiki|last3=Kelly|first3=Jeffery W.|last4=Ikeda|first4=Shu-ichi|title=Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis|journal=Neuroscience Research|volume=56|issue=4|pages=441–449|doi=10.1016/j.neures.2006.08.014|pmid=17028027|year=2006}} 9. ^{{cite journal|last1=Kingsbury|first1=J. S.|last2=Laue|first2=T. M.|last3=Klimtchuk|first3=E. S.|last4=Theberge|first4=R.|last5=Costello|first5=C. E.|last6=Connors|first6=L. H.|title=The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal: DIRECT ANALYSIS BY FLUORESCENCE-DETECTED ANALYTICAL ULTRACENTRIFUGATION|journal=Journal of Biological Chemistry|date=6 March 2008|volume=283|issue=18|pages=11887–11896|doi=10.1074/jbc.M709638200|pmid=18326041|pmc=2335343}} 10. ^{{cite journal|last1=Adamski-Werner|first1=Sara L.|last2=Palaninathan|first2=Satheesh K.|last3=Sacchettini|first3=James C.|last4=Kelly|first4=Jeffery W.|title=Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis|journal=Journal of Medicinal Chemistry|volume=47|issue=2|pages=355–374|doi=10.1021/jm030347n|pmid=14711308|date=January 2004}} 11. ^{{cite journal|last1=Berk|first1=John L.|last2=Suhr|first2=Ole B.|last3=Sekijima|first3=Yoshiki|last4=Yamashita|first4=Taro|last5=Heneghan|first5=Michael|last6=Zeldenrust|first6=Steven R.|last7=Ando|first7=Yukio|last8=Ikeda|first8=Shu-ichi|last9=Gorevic|first9=Peter|last10=Merlini|first10=Giampaolo|last11=Kelly|first11=Jeffrey W.|last12=Skinner|first12=Martha|last13=Bisbee|first13=Alice B.|last14=Dyck|first14=Peter J.|last15=Obici|first15=Laura|title=The Diflunisal Trial: Study accrual and drug tolerance|journal=Amyloid|volume=19|issue=S1|pages=37–38|doi=10.3109/13506129.2012.678509|pmid=22551208|year=2012}} 12. ^{{cite journal|last1=Berk|first1=JL|last2=Suhr|first2=OB|last3=Obici|first3=L|last4=Sekijima|first4=Y|last5=Zeldenrust|first5=SR|last6=Yamashita|first6=T|last7=Heneghan|first7=MA|last8=Gorevic|first8=PD|last9=Litchy|first9=WJ|last10=Wiesman|first10=JF|last11=Nordh|first11=E|last12=Corato|first12=M|last13=Lozza|first13=A|last14=Cortese|first14=A|last15=Robinson-Papp|first15=J|last16=Colton|first16=T|last17=Rybin|first17=DV|last18=Bisbee|first18=AB|last19=Ando|first19=Y|last20=Ikeda|first20=S|last21=Seldin|first21=DC|last22=Merlini|first22=G|last23=Skinner|first23=M|last24=Kelly|first24=JW|last25=Dyck|first25=PJ|last26=Diflunisal Trial|first26=Consortium|title=Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.|journal=JAMA|date=Dec 25, 2013|volume=310|issue=24|pages=2658–67|doi=10.1001/jama.2013.283815|pmid=24368466|pmc=4139164}} External links
4 : Nonsteroidal anti-inflammatory drugs|Salicylic acids|Fluoroarenes|Biphenyls |
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