Diflunisal

Diflunisal

Clinical data
Trade names	Dolobid
Other names	MK647
AHFS/Drugs.com	Monograph
MedlinePlus	a684037
License data	US  DailyMed:  Diflunisal
Pregnancy category	AU:C
Routes of administration	By mouth
ATC code	N02BA11 ( WHO )
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only [1]
Pharmacokinetic data
Bioavailability	80-90%
Protein binding	>99%
Metabolism	Liver
Elimination half-life	8 to 12 hours
Excretion	Kidney
Identifiers
IUPAC name 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid
CAS Number	22494-42-4  Y
PubChem CID	3059
IUPHAR/BPS	7162
DrugBank	DB00861  Y
ChemSpider	2951  Y
UNII	7C546U4DEN
KEGG	D00130  Y
ChEBI	CHEBI:39669  Y
ChEMBL	ChEMBL898  Y
PDB ligand	1FL ( PDBe , RCSB PDB )
CompTox Dashboard (EPA)	DTXSID5022932
ECHA InfoCard	100.040.925
Chemical and physical data
Formula	C13H8F2O3
Molar mass	250.201 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(O)c1cc(ccc1O)c2ccc(F)cc2F
InChI InChI=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) Y Key:HUPFGZXOMWLGNK-UHFFFAOYSA-N Y
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Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. ^[2] It was developed by Merck Sharp & Dohme in 1971, after showing promise in a research project studying more potent chemical analogs of aspirin. ^[3] It was first sold under the brand name Dolobid, by Merck & Co., but generic versions are widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

Medical uses

Diflunisal is indicated for acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. ^[1]

Contraindications

• Hypersensitivity to aspirin/NSAID-induced asthma (AERD) or urticaria
• 3rd trimester pregnancy
• Coronary artery bypass surgery (peri-op pain)

Amyloidosis

Both diflunisal ^{[4] [5]} and several of its analogues ^[6] 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, ^[7] 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. ^[8]

Side effects

In October 2020, the US Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. ^{[9] [10]} They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. ^{[9] [10]}

Mechanism of action

Diflunisal acts by inhibiting the production of prostaglandins, ^[11] hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug. ^[12]

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. ^[13]

Duration of effect

Though 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. ^[12] 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, ^[14] and for acute pain following oral surgery, especially removal of wisdom teeth. ^[15]

Society and culture

Legal status

In April 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Attrogy, intended for the treatment of hereditary transthyretin-mediated amyloidosis in adults with stage 1 or stage 2 polyneuropathy. ^[16] The applicant for this medicinal product is Purpose Pharma International AB. ^[16]

Research

Diflunisal may have some antibacterial activity in vitro against Francisella tularensis live vaccine strain (LVS). ^[17]

References

1. "Dolobid- diflunisal tablet, film coated". DailyMed. 27 August 2024. Retrieved 2 May 2025.
2. Boullard O, Leblanc H, Besson B (2012). "Salicylic Acid". Ullmann's Encyclopedia of Industrial Chemistry . Weinheim: Wiley-VCH. doi:10.1002/14356007.a23_477. ISBN   3527306730.
3. Adams SS (1999). "Ibuprofen, the propionics and NSAIDs: personal reflections over four decades". Inflammopharmacology. 7 (3): 191–7. doi:10.1007/s10787-999-0002-3. PMID   17638090. S2CID   11074565.
4. Tojo K, Sekijima Y, Kelly JW, Ikeda S (December 2006). "Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis". Neuroscience Research. 56 (4): 441–9. doi:10.1016/j.neures.2006.08.014. PMID   17028027. S2CID   42504073.
5. Kingsbury JS, Laue TM, Klimtchuk ES, Théberge R, Costello CE, Connors LH (May 2008). "The modulation of transthyretin tetramer stability by cysteine 10 adducts and the drug diflunisal. Direct analysis by fluorescence-detected analytical ultracentrifugation". The Journal of Biological Chemistry. 283 (18): 11887–96. doi: 10.1074/jbc.M709638200 . PMC   2335343 . PMID   18326041.
6. Adamski-Werner SL, Palaninathan SK, Sacchettini JC, Kelly JW (January 2004). "Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis". Journal of Medicinal Chemistry. 47 (2): 355–74. doi:10.1021/jm030347n. PMID   14711308.
7. Berk JL, Suhr OB, Sekijima Y, Yamashita T, Heneghan M, Zeldenrust SR, et al. (June 2012). "The Diflunisal Trial: study accrual and drug tolerance". Amyloid. 19 (Suppl 1): 37–8. doi:10.3109/13506129.2012.678509. PMID   22551208. S2CID   40303434.
8. Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, et al. (December 2013). "Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial". JAMA. 310 (24): 2658–67. doi:10.1001/jama.2013.283815. PMC   4139164 . PMID   24368466.
9. "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Archived from the original on 16 October 2020. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain .
10. "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Archived from the original on 17 October 2020. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain .
11. Wallace JL (October 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?". Physiological Reviews. 88 (4): 1547–65. doi:10.1152/physrev.00004.2008. PMID   18923189. S2CID   448875.
12. Tempero KF, Cirillo VJ, Steelman SL (February 1977). "Diflunisal: a review of pharmacokinetic and pharmacodynamic properties, drug interactions, and special tolerability studies in humans". British Journal of Clinical Pharmacology. 4 (Suppl 1): 31S –36S. doi:10.1111/j.1365-2125.1977.tb04511.x. PMC   1428837 . PMID   328032.
13. "New Metabolic Pathway Reveals Aspirin-Like Compound's Anti-Cancer Properties. June 2016". Archived from the original on 4 June 2016. Retrieved 9 June 2016.
14. Brogden RN, Heel RC, Pakes GE, Speight TM, Avery GS (February 1980). "Diflunisal: a review of its pharmacological properties and therapeutic use in pain and musculoskeletal strains and sprains and pain in osteoarthritis". Drugs. 19 (2): 84–106. doi:10.2165/00003495-198019020-00002. PMID   6988202. S2CID   24191409.
15. Lawton GM, Chapman PJ (August 1993). "Diflunisal--a long-acting non-steroidal anti-inflammatory drug. A review of its pharmacology and effectiveness in management of postoperative dental pain". Australian Dental Journal. 38 (4): 265–71. doi:10.1111/j.1834-7819.1993.tb05494.x. PMID   8216032.
16. "Attrogy". European Medicines Agency (EMA). 25 April 2025. Retrieved 2 May 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
17. Jayamani E, Tharmalingam N, Rajamuthiah R, Coleman JJ, Kim W, Okoli I, et al. (September 2017). "Characterization of a Francisella tularensis-Caenorhabditis elegans Pathosystem for the Evaluation of Therapeutic Compounds". Antimicrobial Agents and Chemotherapy. 61 (9). doi:10.1128/AAC.00310-17. PMC   5571314 . PMID   28652232.

Further reading

• Moore RA, Derry S, Aldington D, Wiffen PJ (September 2015). "Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews". The Cochrane Database of Systematic Reviews. 2015 (9): CD008659. doi:10.1002/14651858.CD008659.pub3. PMC   6485441 . PMID   26414123.
• Wasey JO, Derry S, Moore RA, McQuay HJ (April 2010). "Single dose oral diflunisal for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews. 2010 (4): CD007440. doi:10.1002/14651858.CD007440.pub2. PMC   4164831 . PMID   20393958.