Triflusal Research Articles

Intractable Progressive Cerebral Infarction with Multiple Atypical Aneurysms in Systemic Lupus Erythematosus

We report a case of intractable progressive cerebral infarction with multiple fusiform aneurysms in a 34-year-old female patient with systemic lupus erythematosus (SLE), non-responsive to massive immunotherapy. The patient visited the emergency department with dysarthria and left-sided hemiparesis that occurred 2 days before. She was diagnosed with SLE involving the brain and received 12 cycles of cyclophosphamide 12 years prior. Brain diffusion-weighted imaging showed acute infarctions involving the pons and medulla. Additionally, multifocal microbleeding-like signals in various cisternal spaces were detected using susceptibility-weighted imaging. Digital subtraction angiography revealed multiple fusiform aneurysms. Despite antithrombotic treatment with trif lusal and immunotherapies, including corticosteroids, mycophenolate mofetil, and immunoglobulins, for cerebral vasculitis associated infarction, her neurologic deficits worsened with recurrent cerebral infarction. Further investigation for accurate diagnosis and treatment is required.

Neuroprotective effect of triflusal and its main metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), in the postischemic brain

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is a metabolite of triflusal (TF), and has been reported to exert anti-inflammatory effect. In this study, the authors investigated whether HTB has a neuroprotective effect against ischemic brain injuries. We showed that intravenous administration of HTB (5mg/kg) 30min before or 1, 3, or 6h after middle cerebral artery occlusion (MCAO) reduced brain infarct to 10.4±3.3%, 16.9±2.3%, 22.2±1.5% and 40.7±7.5%, respectively, of that of treatment-naive MCAO controls, and the therapeutic time window extended to 9h after MCAO (40.7±7.5%). Furthermore, HTB suppressed infarct formation, protected motor activities, and ameliorated neurological deficits more effectively than by TF or salicylic acid (SA). HTB markedly suppressed microglial activation and proinflammatory cytokines expressions in the postischemic brain and in BV2 cells and suppressed LPS-induced nitrite production by inhibiting IkB degradation. In addition, HTB suppressed NMDA-induced neuronal cell death more effectively than TF or SA in primary cortical neuron cultures. Together, these results indicate that HTB has multi-modal protective effects against ischemic brain damage that encompass anti-inflammatory, anti-excitotoxicity, and anti-Zn2+-toxicity effects.

Electrochemical Behavior of Triflusal, Aspirin and their Metabolites at Glassy Carbon and Boron Doped Diamond Electrodes

The electrochemical behavior of triflusal (TRF) and aspirin (ASA), before and after hydrolysis in water and in alkaline medium using two different electrode surfaces, glassy carbon and boron doped diamond, was study by differential pulse voltammetry over a wide pH range. The hydrolysis products are 2-(hydroxyl)-4-(trifluoromethyl)-benzoic acid (HTB) for triflusal and salicylic acid (SA) for aspirin, which in vivo represent their main metabolites. The hydrolysis processes were also followed by spectrophotometry. The UV results showed complete hydrolysis after one hour for TRF and after two hours for ASA in alkaline solution. The glassy carbon electrode enables only indirect determination of TRF and ASA through the electrochemical detection of their hydrolysis products HTB and SA, respectively. The oxidation processes of HTB and SA are pH dependent and involve different numbers of electrons and protons. Moreover, the difference between the oxidation peak potential of SA and HTB was equal to 100 mV in the studied pH range from 1 to 8 due to the CF3 of the aromatic ring of HTB molecule. Due to its wider oxidation potential range, the boron doped diamond electrode was used to study the direct oxidation of TRF and ASA, as well as of their respective metabolites HTB and SA.

Effects of long-chains of zwitterionic micelles on binding constants of triflusal and acetylsalicylic acid

A spectrophotometric study of the reaction of the alkaline hydrolysis of triflusal (TFL) and acetylsalicylic acid (ASA) in the presence of zwitterionic micelles was carried out, with the objective of determining the effects of the hydrophobic and electrostatic interactions on the micellar union of both drugs. A series of zwitterionic surfactants of alkyldimethylammonio propanesulfonate (SB3- n) were used: decyldimethylammonio propanesulfonate (SB3-10), tetradecyldimethylammonio propanesulfonate (SB3-14), hexadecyldimethylammonio propanesulfonate (SB3-16). This reaction is inhibited at higher surfactant concentrations. The experimental data has been processed according to the micellar pseudophase model. The values of the binding constants of both drugs in the micelle ( K S ) determine the importance of the hydrophobic and electrostatic interactions in the micelle solubilization of both drugs.

The study of the influence of surfactant charge on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) using spectrophotometric methods

In this research, the effects of micellar systems on alkaline hydrolysis reactions of acetylsalicylic acid (ASA) and triflusal (TFL) were found to be dependant upon the surfactant charge within the micelle. In cationic micelles, there is a catalytic effect at low concentrations of surfactant. However, this reaction is inhibited at higher surfactant concentrations. In anionic micelles, a catalytic effect occurs, while in zwitterionic and non-ionic micelles there is an inhibitory effect. Such reactions are attributable to changes in reactants on the micellar surface, or to the fact that both reactants are found in different microenvironments. The pseudophase (PS) and ion-exchange (PPIE) models were found to be consistent with the experimental result. Furthermore, the association constants for both drugs could be determined together with micellar rate constants in heterogeneous media.

Response to Letter by Borja et al

Response: We thank Dr Borja and his coauthors for alerting us to the data from trials on triflusal. These trials demonstrate …

Triflusal vs. Aspirin for the Prevention of Infarction: a Randomized Stroke Study (TAPIRSS)

P208 Background: TAPIRSS is a randomized, double-blind, multicenter pilot trial designed to study the efficacy of triflusal for the prevention of secondary ischemic stroke conducted in Buenos Aires, Argentina. Triflusal is an antiplatelet agent structurally related to aspirin. Methods and Results: From October 1996 to October 1999 patients were randomized to group #1 (aspirin therapy, 325 mg/daily) or group #2 (triflusal, 600 mg/daily). All patients had experienced either an ischemic stroke (80.9%) or a transient ischemic attack within 6 months prior to randomization. Patients were treated for a median of 586 days. Data for 429 patients were analyzed. Primary endpoints were: cardiovascular death 3.7%(#1)/2.3%(#2)[OR=1.6]; cerebral ischemic infarction 7.4%(#1)/8.0%(#2)[OR=0.92]; non-fatal myocardial infarction 2.3%(#1)/1.9%(#2)[OR=1.24];severe hemorrhage any kind 3.2%(#1)/0.5%(#2)[OR=7.1][p=0.068]. Secondary endpoints were: non-vascular death 2.4%(#1)/0.5%(#2)[OR=5.02]; non-severe hemorrhage 6.0%(#1)/2.3%(#2)[OR=2.66][p=0.058]; systemic thromboembolism 0.9%(#1)/1.4%(#2)[OR=0.65]. Aggregate analysis of primary endpoints showed no significant differences between aspirin and triflusal. Aggregate analysis of secondary enpoints showed a significant difference in favor of triflusal [p=0.038]. Analysis of the combination severe and non-severe hemorrhage showed a significantly reduced incidence of hemorrhagic events with triflusal [8.3%(#1)/2.8%(#2), p=0.013]. Dyspepsia and gastrointestinal discomfort were the most common adverse events in the triflusal group. Conclusions: Triflusal shows a protective effect similar to aspirin in the prevention of secondary ischemic stroke with a lesser risk of hemorrhagic complications. Also, triflusal may be safe for the primary prevention of ischemic stroke.

TRIFLUSAL VERSUS ASPIRIN IN SECONDARY STROKE PREVENTION:RESULTS OF TACIP STUDY

73 TACIP was a multicentre, double-blind, randomised, parallel trial comparing the efficacy and safety of triflusal (600 mg/od) and ASA (325 mg/od) in patients who had a recent TIA or non disabling stroke. The primary end-point was the combined occurrence of non-fatal stroke, non-fatal AMI or cardiovascular death. Any of them separately was a secondary end-point, as well as total mortality, major systemic or cerebral hemorrhage and systemic thromboembolism. Forty-three centres in Spain and Portugal participated in the trial. A total of 2108 patients were evaluated with a mean follow-up of 31 months. There were no significant differences between both groups regarding to baseline characteristics. Main results were: The incidence of major and minor hemorrhages were higher in ASA than in triflusal group (24.5% vs 16.4%; p Conclusion: Triflusal and low-dose ASA have a similar efficacy in secondary stroke prevention. Major and minor hemorrhages were significantly reduced by triflusal. Triflusal is a safer alternative to aspirin in the secondary prevention of stroke.

Effects and interaction studies of trifusal and other salicylic derivatives on cyclooxygenase in rats

Triflusal (TR) is a new salicylic acid derivative used clinically as an antiplatelet drug. Both aspirin (ASA) and TR inhibit platelet cyclooxygenase but the effects of these drugs are different. TR (0.5–2 mM) strongly inhibited platelet aggregation and malonildialdehyde formation induced by arachidonic acid. The IC 50 was 0.8 mM for TR and less than 0.1 mM for ASA. Deacetylated compounds, salicylic acid (SA) and HTB (the main metabolite of TR) were apparently competitive and reversible inhibitors of cyclooxygenase and HTB was 15 times more potent than SA. They did, however, partially prevent the inhibitory effects of ASA and TR in vitro. A similar effect was observed ex vivo in rats treated with HTB (100 mg/k i.p.) before TR or ASA (20 and 5 mg/kg i.v., respectively). Moreover, TR at 10 and 20 mg/kg i.v., inhibited thromboxane production by more than 50% while its effect on vascular cyclooxygenase was negligible. These findings indicated that TR is a weaker inhibitor of cyclooxygenase than ASA, and that HTB interferes with the effect of TR and ASA, despite the fact that HTB is a more potent reversible inhibitor than SA with probably a higher affinity for this enzyme.