Diflunisal

Diflunisal
Clinical data
Trade names	Dolobid
AHFS/Drugs.com	Monograph
MedlinePlus	a684037
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: WARNINGRx-only;
Pharmacokinetic data
Bioavailability	80-90%
Protein binding	>99%
Metabolism	Hepatic
Elimination half-life	8 to 12 hours
Excretion	Renal
Identifiers
	IUPAC name 2',4'-difluoro-4-hydroxybiphenyl-3-carboxylic acid;
CAS Number	22494-42-4 ;
PubChem CID	3059;
IUPHAR/BPS	7162;
DrugBank	DB00861 ;
ChemSpider	2951 ;
UNII	7C546U4DEN;
KEGG	D00130 ;
ChEBI	CHEBI:39669 ;
ChEMBL	ChEMBL898 ;
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) ; Key:HUPFGZXOMWLGNK-UHFFFAOYSA-N ;
	(verify)

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity.^[2] 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.^[3] 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 action

Like all NSAIDs, diflunisal acts by inhibiting the production of prostaglandins,^[4] hormones which are involved in inflammation and pain. Diflunisal also has an antipyretic effect, but this is not a recommended use of the drug.^[5]

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.^[6]

It has been reported that diflunisal has some antibacterial activity in vitro against Francisella tularensis live vaccine strain (LVS).^[7]

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.^[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,^[8] and for acute pain following oral surgery, especially removal of wisdom teeth.^[9]

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

Pain, mild to moderate
Osteoarthritis
Rheumatoid arthritis
Injury to tendons
Inflammation
ATTR amyloidosis

Amyloidosis

Both diflunisal^[10]^[11] and several of its analogues^[12] 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,^[13] 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.^[14] However a significantly larger Phase III trial would be needed to prove the drugs effectiveness for treating this condition.

Side effects

In October 2020, the U.S. 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.^[15]^[16] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.^[15]^[16]

Gastrointestinal

The 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.

Increased risk of GI events including bleeding, ulceration, and stomach or intestine perforation.
Abdominal pain or cramps
Constipation
Gas
Diarrhea
Nausea and vomiting
Dyspepsia

Cardiovascular

Irregular heart beat
Possible increased risk of serious and potentially fatal cardiovascular thrombotic events, MI, and stroke
Risks may increase with duration of use and for cardiovascular disease history

Ear, nose, throat, and eye

Ringing in the ears
Yellowing of eyes

Central nervous system

Drowsiness
Dizziness
Headache
Insomnia
Fatigue
Somnolence
Nervousness

Skin

Swelling of the feet, ankles, lower legs, and hands
Yellowing of skin
Rash
Ecchymosis

Contraindications

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

Cautions

^{[citation needed]}

Cardiovascular diseases
Cardiac risk factors
Hypertension
Congestive heart failure
Elderly or debilitated
Impaired liver function
Impaired kidney function
Dehydration
Fluid retention
History of gastrointestinal bleeds/PUD
Asthma
Coagulopathy
Smoker (tobacco use)
Corticosteriod use
Anticoagulant use
Alcohol use
Diuretic use
ACE inhibitor use

Overdose

Deaths 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.

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ 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.
^ 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.
^ 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.
^ ^a ^b 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.
^ "New Metabolic Pathway Reveals Aspirin-Like Compound's Anti-Cancer Properties. June 2016". Archived from the original on 2016-06-04. Retrieved 2016-06-09.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^a ^b "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. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.
^ ^a ^b "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.

External links

Diflunisal: MedlinePlus Drug Information
Dolobid Prescribing Information (manufacturer's website)
Dolobid Medication Guide (manufacturer's website)
"Single dose oral diflunisal for acute postoperative pain in adults" Archived 2010-05-21 at the Wayback Machine

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[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] 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.

[Tempero1977-5] 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.

[6] "New Metabolic Pathway Reveals Aspirin-Like Compound's Anti-Cancer Properties. June 2016". Archived from the original on 2016-06-04. Retrieved 2016-06-09.

[7] 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.

[8] 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.

[9] 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.

[10] 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.

[11] 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.

[12] 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.

[13] 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.

[14] 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.

[FDA_PR_20201015-15] "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. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.

[FDA_safety_20201015-16] "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.

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