Identification

Name
Triflusal
Accession Number
DB08814
Type
Small Molecule
Groups
Approved, Investigational
Description

Triflusal is a 2-acetoxy-4-trifluoromethylbenzoic acid and it is an aspirin chemically-related molecule but not a derivative. The benefits of this agent are the lack of action over the arachidonic acid pathway, the driven production of nitric oxide and the increase of cyclic nucleotide concentration on endothelial cells. The latest translates into the expansion of peripheral blood vessels.[11] It is very important as a secondary prevention of ischemic stroke by offering a lower risk of bleeding.[12] It was developed by J. Uriach and Company and even though it is commercialized in different countries it is not approved by the FDA, EMA or HealthCanada.

Structure
Thumb
Synonyms
  • Triflusal
Categories
UNII
1Z0YFI05OO
CAS number
322-79-2
Weight
Average: 248.157
Monoisotopic: 248.029643194
Chemical Formula
C10H7F3O4
InChI Key
RMWVZGDJPAKBDE-UHFFFAOYSA-N
InChI
InChI=1S/C10H7F3O4/c1-5(14)17-8-4-6(10(11,12)13)2-3-7(8)9(15)16/h2-4H,1H3,(H,15,16)
IUPAC Name
2-(acetyloxy)-4-(trifluoromethyl)benzoic acid
SMILES
CC(=O)OC1=C(C=CC(=C1)C(F)(F)F)C(O)=O

Pharmacology

Indication

Triflusal is indicated as prophylaxis of thromboembolic disorders.[15] It has been registered in Spain and in other countries of Europe, South America and South Korea for the prevention of Stroke and myocardial infarction.[14]

Pharmacodynamics

Triflusal is an antithrombotic anticoagulant. It irreversibly inhibits the production of thromboxane-B2 in platelets by acetylating cycloxygenase-1. Triflusal affects many other targets such as NF kappa B, which is a gene expression regulatory factor for cycloxygenase-a and cytokines. Numerous studies comparing the efficacy and safety profile (i.e. systemic hemorrhage) between triflusal and acetylsalsylic acid has shown either no significant difference or a better effacy and safety profile for triflusal. Triflusal has been shown to protect cerebral tissue due to its inhibition of lipid peroxidation resulting from anoxia-reoxygenation.[1]

Mechanism of action

Triflusal is chemically related to acetylsalicylic acid (ASA) and irreversibly inhibits cycloxygenase-1 (COX-1) in platelets. Acetylation of the active group of COX-1 prevents the formation of thromboxane-B2 in platelets. However, it is unique because it spares the arachidonic acid metabolic pathway in endothelial cells. In addition, it favors the production of nitric oxide, a vasodilator.[5]

TargetActionsOrganism
AProstaglandin G/H synthase 1
antagonist
Human
ANuclear factor NF-kappa-B p105 subunit
antagonist
Human
ANitric oxide synthase, inducible
agonist
Human
AcAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
antagonist
Human
Absorption

Absorbed in the small intestine with a bioavailability range from 83% to 100%. There is no significant difference between the absorption of the oral solution and capsule formulation.[2] Triflusal displays a Cmax of 11.6 mcg/ml and a tmax of 0.88 h. The major metabolite of triflusal presents different pharmacokinetic properties by showing a Cmax and tmax of 92.7 mcg/ml and 4.96 h, respectively.[13]

Volume of distribution

The reported volume of distribution for triflusal is of 34L.[13]

Protein binding

Triflusal binds almost completely to plasma proteins reaching a 99% of the administered dose.[L1186]

Metabolism

In the liver, triflusal undergoes deacetylation, forming its main metabolite 2-OH-4-trifluoromethyl benzoic acid (HTB). This major metabolite seems to have marked antiplatelet properties in vitro.[14]

Route of elimination

The elimination pathway of triflusal is primarily renal. Urine analysis has shown the presence of unchanged triflusal, HTB and the glycine conjugate of HTB.[L1186]

Half life

In the healthy human, the half-life is 0.5 +/- 0.1h, while that of HTB is 34.3 +/- 5.3h.[L1186]

Clearance

Renal clearance is 0.8 +/- 0.2L/h and 0.18 +/1 0.04L/h for triflusal and HTB, respectively.[L1186]

Toxicity

There is the possibility of producing major systemic hemorrhages.[L1168]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Triflusal.
AcenocoumarolAcenocoumarol may increase the anticoagulant activities of Triflusal.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Triflusal.
AloxiprinThe risk or severity of adverse effects can be increased when Triflusal is combined with Aloxiprin.
AlteplaseThe risk or severity of bleeding can be increased when Alteplase is combined with Triflusal.
Aminosalicylic AcidThe risk or severity of bleeding can be increased when Aminosalicylic Acid is combined with Triflusal.
AnagrelideThe risk or severity of bleeding can be increased when Anagrelide is combined with Triflusal.
AncrodTriflusal may increase the anticoagulant activities of Ancrod.
AndrographolideAndrographolide may increase the anticoagulant activities of Triflusal.
AnistreplaseTriflusal may increase the anticoagulant activities of Anistreplase.
Food Interactions
  • Gingko bilboa
  • Herbs with anticoagulant/antiplatelet activity such as alfalfa, feverfew, ginger, ginseng, grape seed, green tea, horseradish

References

General References
  1. Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P: Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009 May-Jun;50(3):199-207. [PubMed:19465361]
  2. Izquierdo I, Borja J, Rovira S, Pelagio P, Torres F, Cebrecos J, Garcia-Rafanell J: Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjects. A single, randomized, two-way cross-over, open-label phase I study. Arzneimittelforschung. 2010;60(1):36-41. doi: 10.1055/s-0031-1296246. [PubMed:20184225]
  3. Duran X, Sanchez S, Vilahur G, Badimon L: Protective effects of triflusal on secondary thrombus growth and vascular cyclooxygenase-2. J Thromb Haemost. 2008 Aug;6(8):1385-92. doi: 10.1111/j.1538-7836.2008.03036.x. Epub 2008 May 22. [PubMed:18503633]
  4. Quetglas EG, Campanero MA, Sadaba B, Escolar M, Azanza JR: Bioequivalence of two oral formulations of triflusal capsules in healthy volunteers. Arzneimittelforschung. 2008;58(6):283-7. doi: 10.1055/s-0031-1296508. [PubMed:18677970]
  5. Gonzalez-Correa JA, De La Cruz JP: Triflusal: an antiplatelet drug with a neuroprotective effect? Cardiovasc Drug Rev. 2006 Spring;24(1):11-24. [PubMed:16939630]
  6. Fraj J, Valero A, Vives R, Perez I, Borja J, Izquierdo I, Picado C: Safety of triflusal (antiplatelet drug) in patients with aspirin-exacerbated respiratory diseases. Allergy. 2008 Jan;63(1):112-5. [PubMed:18053020]
  7. Sanchez-Machin I, Garcia Robaina JC, Torre Morin F: Widespread eczema from triflusal confirmed by patch testing. Contact Dermatitis. 2004 Apr;50(4):257. [PubMed:15186390]
  8. Matias-Guiu J, Ferro JM, Alvarez-Sabin J, Torres F, Jimenez MD, Lago A, Melo T: Comparison of triflusal and aspirin for prevention of vascular events in patients after cerebral infarction: the TACIP Study: a randomized, double-blind, multicenter trial. Stroke. 2003 Apr;34(4):840-8. Epub 2003 Mar 20. [PubMed:12649515]
  9. Culebras A, Rotta-Escalante R, Vila J, Dominguez R, Abiusi G, Famulari A, Rey R, Bauso-Tosselli L, Gori H, Ferrari J, Reich E: Triflusal vs aspirin for prevention of cerebral infarction: a randomized stroke study. Neurology. 2004 Apr 13;62(7):1073-80. [PubMed:15079004]
  10. Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabin J, Torres F: Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004296. [PubMed:16034926]
  11. Shin S, Kim KJ, Cho IJ, Hong GR, Jang Y, Chung N, Rah YM, Chang HJ: Effect of Triflusal on Primary Vascular Dysregulation Compared with Aspirin: A Double-Blind, Randomized, Crossover Trial. Yonsei Med J. 2015 Sep;56(5):1227-34. doi: 10.3349/ymj.2015.56.5.1227. [PubMed:26256964]
  12. Han SW, Kim YJ, Ahn SH, Seo WK, Yu S, Oh SH, Nam HS, Choi HY, Yoon SS, Kim SH, Lee JY, Lee JH, Hwang YH, Lee KO, Jung YH, Lee J, Sohn SI, Kim YN, Lee KA, Bushnell CD, Lee KY: Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping. J Stroke. 2017 Sep;19(3):356-364. doi: 10.5853/jos.2017.01249. Epub 2017 Sep 29. [PubMed:29037010]
  13. Ramis J, Mis R, Forn J, Torrent J, Gorina E, Jane F: Pharmacokinetics of triflusal and its main metabolite HTB in healthy subjects following a single oral dose. Eur J Drug Metab Pharmacokinet. 1991 Oct-Dec;16(4):269-73. [PubMed:1823870]
  14. Bogousslavsky J. (2001). Drug Therapy for Stroke Prevention. Taylor and Francis.
  15. MIMS [Link]
External Links
PubChem Compound
9458
PubChem Substance
347827803
ChemSpider
9086
ChEBI
94721
ChEMBL
CHEMBL1332032
Wikipedia
Triflusal
ATC Codes
B01AC18 — Triflusal
MSDS
Download (245 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedBasic ScienceHealthy Volunteers2
2CompletedTreatmentInsulin Resistance1
4CompletedHealth Services ResearchAtherothrombosis1
4CompletedTreatmentCerebral Infarctions1
4CompletedTreatmentVasospastic Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)114-117ºC'MSDS'
water solubility<1 mg/ml'MSDS'
logP2.231'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.696 mg/mLALOGPS
logP2.4ALOGPS
logP2.12ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)3.39ChemAxon
pKa (Strongest Basic)-7.1ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area63.6 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity50.42 m3·mol-1ChemAxon
Polarizability19.32 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as acylsalicylic acids. These are o-acylated derivatives of salicylic acid.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Acylsalicylic acids
Alternative Parents
Trifluoromethylbenzenes / Phenol esters / Benzoic acids / Phenoxy compounds / Benzoyl derivatives / Dicarboxylic acids and derivatives / Carboxylic acid esters / Carboxylic acids / Organofluorides / Organic oxides
show 3 more
Substituents
Acylsalicylic acid / Trifluoromethylbenzene / Phenol ester / Benzoic acid / Phenoxy compound / Benzoyl / Dicarboxylic acid or derivatives / Carboxylic acid ester / Carboxylic acid derivative / Carboxylic acid
show 10 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P: Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009 May-Jun;50(3):199-207. [PubMed:19465361]
  2. Dominguez MJ, Vacas M, Saez Y, Olabarria I, Velasco A, Iriarte JA, Forn J: Effects of triflusal in patients with prosthetic heart valves. Clin Ther. 1985;7(3):357-60. [PubMed:3838919]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Transcriptional repressor activity, rna polymerase ii transcription regulatory region sequence-specific binding
Specific Function
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related...
Gene Name
NFKB1
Uniprot ID
P19838
Uniprot Name
Nuclear factor NF-kappa-B p105 subunit
Molecular Weight
105355.175 Da
References
  1. Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F, Schneider A, Schwaninger M: Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab. 2005 Jan;25(1):30-40. [PubMed:15678110]
  2. Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P: Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009 May-Jun;50(3):199-207. [PubMed:19465361]
  3. Gomez-Isla T, Blesa R, Boada M, Clarimon J, Del Ser T, Domenech G, Ferro JM, Gomez-Anson B, Manubens JM, Martinez-Lage JM, Munoz D, Pena-Casanova J, Torres F: A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis Assoc Disord. 2008 Jan-Mar;22(1):21-9. doi: 10.1097/WAD.0b013e3181611024. [PubMed:18317243]
  4. Whitehead SN, Bayona NA, Cheng G, Allen GV, Hachinski VC, Cechetto DF: Effects of triflusal and aspirin in a rat model of cerebral ischemia. Stroke. 2007 Feb;38(2):381-7. Epub 2006 Dec 28. [PubMed:17194886]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity ...
Gene Name
NOS2
Uniprot ID
P35228
Uniprot Name
Nitric oxide synthase, inducible
Molecular Weight
131116.3 Da
References
  1. Anninos H, Andrikopoulos G, Pastromas S, Sakellariou D, Theodorakis G, Vardas P: Triflusal: an old drug in modern antiplatelet therapy. Review of its action, use, safety and effectiveness. Hellenic J Cardiol. 2009 May-Jun;50(3):199-207. [PubMed:19465361]
  2. Sanchez de Miguel L, Casado S, Farre J, Garcia-Duran M, Rico LA, Monton M, Romero J, Bellver T, Sierra MP, Guerra JI, Mata P, Esteban A, Lopez-Farre A: Comparison of in vitro effects of triflusal and acetysalicylic acid on nitric oxide synthesis by human neutrophils. Eur J Pharmacol. 1998 Feb 5;343(1):57-65. [PubMed:9551715]
  3. De Miguel LS, Jimenez A, Monton M, Farre J, Del Mar Arriero M, Rodriguez-Feo JA, Garcia-Canete J, Rico L, Gomez J, Nunez A, Casado S, Farre AL: A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function. Eur J Clin Invest. 2000 Sep;30(9):811-7. [PubMed:10998082]
  4. Gonzalez-Correa JA, De La Cruz JP: Triflusal: an antiplatelet drug with a neuroprotective effect? Cardiovasc Drug Rev. 2006 Spring;24(1):11-24. [PubMed:16939630]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Metal ion binding
Specific Function
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient wit...
Gene Name
PDE10A
Uniprot ID
Q9Y233
Uniprot Name
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Molecular Weight
88411.71 Da
References
  1. McNeely W, Goa KL: Triflusal. Drugs. 1998 Jun;55(6):823-33; discussion 834-5. [PubMed:9617597]
  2. De Miguel LS, Jimenez A, Monton M, Farre J, Del Mar Arriero M, Rodriguez-Feo JA, Garcia-Canete J, Rico L, Gomez J, Nunez A, Casado S, Farre AL: A 4-trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function. Eur J Clin Invest. 2000 Sep;30(9):811-7. [PubMed:10998082]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. JCcardiol [Link]

Drug created on June 28, 2011 23:05 / Updated on October 08, 2018 21:35