salicylates and triflusal

Stroke is a leading cause of death worldwide and the first cause of disability in the Western world. Over the last 20 years, antiplatelet agents have reduced overall stroke rates in primary and secondary prevention in men. However, this has not been the case for women. In this narrative review, the most widely used antiplatelet therapies for primary and secondary prevention in stroke, excluding cardioembolic stroke, will be outlined. First, the largest randomised controlled trials will be analysed as well as the enrolment percentages of women. Second, analyses on sex-interaction effects in each study will be examined. Moreover, the Authors will discuss the need to develop targeted antiplatelet therapies specifically for women. Based on current results, the most randomised clinical trials and meta-analyses on antiplatelet agents in cerebrovascular disease have not performed sub-analyses on sex-related differences and this is mainly because women were underrepresented. Despite this, antiplatelet agents are considered to be equally effective for both sexes in primary and secondary stroke prevention. Finally, aspirin is the most widely studied antiplatelet in women and has been shown to provide greater benefit for women as primary prevention of ischemic stroke without a significant increased risk in haemorrhage.

Topics: Aspirin; Clopidogrel; Dipyridamole; Drug Therapy, Combination; Female; Humans; Naphthalenes; Platelet Aggregation Inhibitors; Primary Prevention; Propionates; Salicylates; Secondary Prevention; Sex Factors; Stroke; Ticlopidine

Triflusal (Aflen, Disgren, Tecnosal, Triflux) is a novel platelet antiaggregant with structural similarities to salicylates, but which is not derived from aspirin. It has similar efficacy to aspirin in patients with cerebral or myocardial infarction, but has a reduced risk of haemorrhagic complications. In addition, triflusal plus moderate-intensity anticoagulation has demonstrated efficacy when used as thromboprophylaxis in atrial fibrillation. As such, triflusal has a role in the primary prevention of cerebrovascular events in atrial fibrillation, and for the secondary prevention of cerebral and myocardial infarction, primarily as an alternative to aspirin in patients for whom aspirin is unsuitable.

Topics: Atrial Fibrillation; Cardiovascular Diseases; Cerebral Infarction; Drug Interactions; Humans; Meta-Analysis as Topic; Myocardial Infarction; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Salicylates; Thromboembolism

Triflusal is a derivative of salicylic acid with a well-established platelet aggregation inhibitory profile. Its pharmacokinetic and pharmacodynamic properties differ, however, somewhat from those of acetylsalicylic acid. A number of recent experimental and clinical studies have shown that triflusal is a potentially useful choice in the treatment and prophylaxis of brain ischemia because of its antithrombogenic as well as neuroprotective effects. Its antithrombogenic effect has been demonstrated at the clinical as well as at the experimental level, while its neuroprotective effect has been shown only in experimental models. The drug interferes with thrombogenesis by inhibiting thromboxane synthesis and increasing the levels of cAMP and nitric oxide. Its neuroprotective action is the result of its antioxidant and antiinflammatory effects in brain tissue. From a clinical standpoint triflusal is similar in efficacy to acetylsalicylic acid in preventing stroke, but has less adverse effects, especially it is less likely to cause bleeding. Because of its pharmacodynamic properties and lower rate of adverse reactions, triflusal may be a useful alternative to acetylsalicylic acid in the prevention of stroke.

Topics: Animals; Biological Availability; Clinical Trials as Topic; Female; Humans; Male; Neuroprotective Agents; Platelet Aggregation Inhibitors; Salicylates; Stroke; Tissue Distribution

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.

Topics: Anticoagulants; Aspirin; Clopidogrel; Dipyridamole; Drug Interactions; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Salicylates; Stroke; Ticlopidine; Warfarin

Aspirin is the standard treatment for secondary prevention of stroke and other vascular events. Several studies suggest that triflusal may have a better safety profile.. To determine in people at high risk of vascular events whether triflusal is an effective and safe treatment for primary and secondary prevention of serious vascular events.. We searched the trials registers of the following Cochrane Review Groups: Stroke Group (last searched October 2004), Heart Group, Peripheral Vascular Diseases Group and Metabolic and Endocrine Disorders Group (last searched May 2003). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2003), MEDLINE (1977 to 2003) and EMBASE (1980 to 2003). We searched reference lists and contacted researchers in the field, authors of relevant trials and the drug manufacturer.. Randomised and quasi-randomised studies comparing triflusal with placebo or aspirin in people at high risk of vascular events.. Two authors independently assessed trial quality and extracted data. The primary outcome was a serious vascular event (non-fatal acute myocardial infarction (AMI), non-fatal ischemic or hemorrhagic stroke, or vascular death). Other efficacy and safety measures collected were frequency of different vascular events, adverse events, minor and major hemorrhages.. (1) Aspirin versus triflusal: five studies enrolled patients with stroke or transient ischemic attack (TIA) (4 trials; 2944 patients; followed for 6 to 47 months) or AMI (one trial; 2275 patients; followed for 35 days). Entry criteria were similar within each subgroup of patients. Patient groups were appropriately selected and well matched. The primary outcome in all trials was a composite outcome of vascular events. Trials had no important bias except in one study (217 patients). For the primary outcome of a serious vascular event there was no significant difference between triflusal and aspirin; the odds ratio (OR) was 1.04 (95% confidence interval (CI) 0.87 to 1.23). Significant differences were found for frequency of hemorrhages, both minor (OR 1.60, 95% CI 1.31 to 1.95) and major (OR 2.34, 95% CI 1.58 to 3.46) and for non-hemorrhagic gastrointestinal adverse events (OR 0.84, 95% CI 0.75 to 0.95). Sensitivity analysis of well versus poorly allocated trials showed no significant differences. (2) Triflusal versus placebo: two trials enrolled patients with unstable angina (281 patients) or peripheral arteriopathy (122 patients), who were followed for 6 months. Triflusal was associated with a reduction in serious vascular events (OR 2.29, 95% CI 1.01 to 5.19; OR greater than 1 favours triflusal) and with a higher frequency of adverse events (OR 1.68, 95% CI 1.00 to 2.80).. No significant differences were found between triflusal and aspirin for secondary prevention of serious vascular events in patients with stroke or TIA and AMI. However, our review cannot exclude moderate differences in efficacy. Triflusal was associated with a lower risk of hemorrhagic complications.

Topics: Aspirin; Humans; Ischemic Attack, Transient; Myocardial Infarction; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Salicylates; Stroke

Patients experiencing stroke or transient ischemic attack (TIA) are at high risk for recurrent (secondary) strokes, which comprise 29% of all strokes in the United States. Current recommendations for prevention of secondary stroke from the American College of Chest Physicians (ACCP) call for the broad use of platelet antiaggregation (antiplatelet) agents for patients with a history of noncardioembolic stroke or TIA. Five agents--aspirin, ticlopidine, clopidogrel, extended-release dipyridamole (ER-DP), and triflusal--have demonstrated efficacy in large-scale clinical studies in the prevention of recurrent vascular events and/or stroke in patients with a history of stroke. The results of the following studies are reviewed and compared: the Swedish Aspirin Low-Dose Trial (SALT), the United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial, Dutch Transient Ischemic Attack (Dutch TIA) study (aspirin), the Canadian American Ticlopidine Study (CATS), the Ticlopidine Aspirin Stroke Study (TASS), the African American Antiplatelet Stroke Prevention Study (AAASPS) (ticlopidine), the Clopidogrel versus Aspirin in Patients at Risk of Recurrent Ischemic Events (CAPRIE) trial, the Management of Atherothrombosis With Clopidogrel in High-Risk Patients study (MATCH) (clopidogrel), the second European Stroke Prevention Study (ESPS2) (aspirin plus ER-DP), and the Triflusal versus Aspirin in Cerebral Infarction Prevention (TACIP) study. In comparative monotherapy studies of patients with previous stroke, ticlopidine demonstrates statistically significant improved efficacy over aspirin, and clopidogrel demonstrates nonsignificant slight improvement over aspirin for the prevention of ischemic cardiac and cerebrovascular events; however, the adverse event profile of ticlopidine (including rash, diarrhea, and neutropenia) will probably limit its long-term use. Among combination approaches, only aspirin plus ER-DP has demonstrated statistically significant, clinically meaningful additive benefit over monotherapy with each agent. Clopidogrel plus aspirin did not significantly improve preventive efficacy and increased the risk of serious side effects, including life-threatening bleeding episodes. The 15,500-patient PRoFESS (the Prevention Regimen for Effectively Avoiding Second Strokes) study, with results expected in 2008, will directly compare aspirin plus ER-DP with clopidogrel monotherapy for the prevention of recurrent stroke and should provide statistically robust esti

Topics: Aspirin; Clopidogrel; Dipyridamole; Humans; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Stroke; Ticlopidine

Triflusal is an antiplatelet agent structurally related to the salicylate group of compounds, but it is not derived from aspirin (acetylsalicylic acid). Platelet antiaggregant properties of triflusal and its active 3-hydroxy-4-trifluoro-methylbenzoic acid metabolite are primarily mediated by specific inhibition of platelet arachidonic acid metabolism. Triflusal, compared with placebo for 6 months, significantly reduced the incidence of nonfatal myocardial infarction in patients with unstable angina. In patients with peripheral arteriopathy, total and pain free walking distances were markedly improved in triflusal compared with placebo recipients. The cumulative event rate for stroke, ischemic cardiopathy and vascular death was lower, but not significantly different, in patients with atherothrombotic stroke who received triflusal than in aspirin recipients. Differences were significant, and favoured triflusal, in a subgroup of patients with > 70% carotid stenosis. Prophylaxis with triflusal for 6 months after aortocoronary vein grafting reduced the number of new distal anastomosis occlusions and the graft attrition rate more than aspirin or placebo. The incidence of deep vein thrombosis or pulmonary embolism in more than 500 patients undergoing hip surgery was similar for these 3 treatments. The amount of blood transfused was significantly reduced in triflusal compared with aspirin recipients who underwent hip surgery. Risk of haemorrhage was also reduced in ischemic stroke patients receiving triflusal versus aspirin.

Topics: Adult; Angina Pectoris; Animals; Aspirin; Carotid Stenosis; Humans; In Vitro Techniques; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Complications; Pulmonary Embolism; Randomized Controlled Trials as Topic; Salicylates; Thrombophlebitis

Different studies have shown that aspirin (AAS), in low doses, may lead to a considerable frequency of hemorrhagic complications when used in the long term.. We compare the long-term occurrence of hemorrhagic complications with low doses of AAS and high doses of triflusal.. Our series included 106 patients who took 900 mg triflusal per day (300 mg 3 times per day) and 111 who took AAS (330 mg/day once daily). The former were followed up for an average period of 48.3 months (20-94) and the latter for 46.3 months (2-84). The average follow-up period for the study was 47.3 months. The presence of hemorrhagic complications was evaluated, as was their frequency and follow-up curve.. Compared with AAS, triflusal led to a 76% reduction in risk of hemorrhagic complications (2.8% against 10.8%; OR 0.24; IC 0.06-0.94). There was a slightly increased incidence of hemorrhages in the women's group. There were more hemorrhages than gastrointestinal hemorrhages (4.5% against 0.9%) and intracranial hemorrhages (1.8%-0.9%). The follow-up curve showed significant differences in the form of an increased risk of hemorrhagic complications with AAS.. The risk of hemorrhage with AAS depended on the period of follow-up, in a similar manner to with oral anticoagulant agents, in patients with prophylaxis of cerebral infarct. On the other hand, this did not occur with triflusal, with which the risk was homogeneous and lower in the long term.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cerebral Infarction; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Factors; Salicylates; Sex Factors; Time Factors

Triflusal has demonstrated an efficacy similar to aspirin in the prevention of vascular events in patients with acute myocardial infarction (ΜΙ) and ischaemic stroke but with less bleeding events.. We performed a randomised, multicentre, phase 4 clinical trial to compare the clinical efficacy and safety of triflusal versus aspirin, administered for 12 months in patients eligible to receive a cyclooxygenase-1 (COX-1) inhibitor.. Patients with stable coronary artery disease or with a history of non-cardioembolic ischaemic stroke were randomly assigned to receive either triflusal 300 mg twice or 600 mg once daily or aspirin 100 mg once daily for 12 months. The primary efficacy endpoint was the composite of: (a) ΜΙ, (b) stroke (ischaemic or haemorrhagic), or, (c) death from vascular causes for the entire follow-up period. The primary safety endpoints were the rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria.. At 12-month follow-up, an equivalent result was revealed between the triflusal (n=559) and aspirin (n=560) in primary efficacy endpoint. Specifically, the combined efficacy outcome rate (i.e. MI, stroke or death from vascular causes) difference was equal to -1.3% (95% confidence interval -1.1 to 3.5) and lied within the a-priori defined equivalence interval (p<0.001). Regarding the primary safety endpoints, patients on triflusal treatment were 50% less likely to develop bleeding events according to the BARC criteria, and especially any clinically overt sign of haemorrhage that requires diagnostic studies, hospitalisation or special treatment (BARC type 2).. The efficacy of triflusal in the secondary prevention of vascular events is similar to aspirin when administered for 12 months. Importantly, triflusal significantly reduced the incidence of ΜΙ and showed a better safety profile compared with aspirin. (ASpirin versus Triflusal for Event Reduction In Atherothrombosis Secondary prevention, ASTERIAS trial; Clinical Trials.gov Identifier: NCT02616497).

Topics: Aged; Aspirin; Brain Ischemia; Coronary Artery Disease; Cyclooxygenase Inhibitors; Female; Greece; Hemorrhage; Humans; Intracranial Embolism; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Risk Factors; Salicylates; Secondary Prevention; Stroke; Time Factors; Treatment Outcome

The antiplatelet effect of clopidogrel is reportedly influenced by cytochrome P450 2C19 (CYP2C19) polymorphisms. However, there is no data concerning the relationship between stroke recurrence and CYP2C19 polymorphisms in patients treated with clopidogrel for secondary prevention of ischemic stroke. Triflusal may be an alternative therapy for clopidogrel in patients with poor genotype. The Comparison of Triflusal and Clopidogrel Effects in Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping (MAESTRO) study will investigate the effect of antiplatelet agents based on CYP2C19 polymorphisms in secondary prevention of ischemic stroke.. Assuming that 55% of patients belong to the poor genotype group, the required sample size is 1080 patients with at least 24 months of follow-up. This study is designed as a prospective, multicenter, randomized, parallel-group, open-label, and blind genotype trial. Patients who experience their first non-cardiogenic ischemic stroke within 30 days prior to screening are eligible. Patients received 300 mg triflusal twice a day or 75 mg clopidogrel once daily during the trial. The study is registered with ClinicalTrials.gov (NCT01174693).. The primary outcome is recurrent ischemic stroke or hemorrhagic stroke. Secondary outcomes consist of composite major vascular events including stroke, myocardial infarction, coronary revascularization, or vascular death.. Personalized medicine may be essential for patients according to individual drug metabolism abilities. MAESTRO is the first prospective study designed to evaluate the effect of CYP2C19 polymorphism in secondary stroke prevention and will resolve several questions regarding preventive antiplatelet agents for recurrent stroke.

Topics: Brain Ischemia; Cerebral Hemorrhage; Chemoprevention; Clopidogrel; Cytochrome P-450 CYP2C19; Follow-Up Studies; Genotype; Humans; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Secondary Prevention; Single-Blind Method; Stroke; Ticlopidine; Treatment Outcome

The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions.. The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography.. The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxμg/mL for the fasting state and 22.20, 5,038 hxμg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 hxμg/mL for the fasting state and 22.44, 5,632 hxμg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB.. High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Biotransformation; Capsules; China; Cross-Over Studies; Dietary Fats; Fasting; Female; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Platelet Aggregation Inhibitors; Postprandial Period; Salicylates; Therapeutic Equivalency; Young Adult

Primary vascular dysregulation (PVD) is a condition in which the response to cold temperature or external stimuli is abnormal. We investigated whether triflusal use results in amelioration of PVD symptoms and improvement of several related parameters compared with aspirin.. Eighty-eight PVD patients (54% female, 56±8 years) were randomly selected to receive either triflusal (300 mg, b.i.d.) or aspirin (150 mg, b.i.d.) for a period of 6 weeks followed by crossover. PVD was defined as both red-blood-cell standstill in video-assisted microscopic capillaroscopy during cold stimulation using carbon dioxide gas and a score of more than 7 points in a validated questionnaire. Efficacy of treatment was assessed by 1) cold intolerance symptom severity (CISS) score, 2) finger Doppler indices, and 3) indocyanine green perfusion imaging.. The use of triflusal resulted in a greater improvement in CISS score (44.5±18.4 vs. 51.9±16.2; p<0.001) and in mean radial peak systolic velocity (69.8±17.2 vs. 66.1±16.4; p=0.011) compared to aspirin. Furthermore, significant differences were also observed in perfusion rates on indocyanine green perfusion imaging between triflusal and aspirin (45.6±25.8 vs. 51.6±26.9; p=0.020).. Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin.

Topics: Adult; Aspirin; Cardiovascular Diseases; Cross-Over Studies; Double-Blind Method; Female; Humans; Indocyanine Green; Male; Middle Aged; Perfusion Imaging; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Treatment Outcome

Triflusal presents comparable antiplatelet activity to aspirin while presenting a more favourable safety profile, and is used in the treatment of thrombosis. The study aimed to evaluate the pharmacokinetics and safety of triflusal and its major metabolite 2-(hydroxyl)-4-(trifluoromethyl)- benzoic acid (HTB) in healthy Chinese subjects.30 healthy subjects were recruited in this randomized, single-center, and open-label, parallel, single ascending doses (300, 600, 900 mg) and multiple doses (600 mg, once daily for 7 days) study. Plasma samples were analyzed with a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. Safety was assessed by adverse events, ECG, laboratory testing, and vital signs.Triflusal was safe and well tolerated. After single-dose administration, triflusal was rapidly absorbed with a mean Tmax of 0.55-0.92 h and a mean t1/2 kel of 0.35-0.65 h, HTB was absorbed with a mean Tmax of 2.35-3.03 h and a mean t1/2 kel of 52.5-65.57 h. Cmax and AUC for triflusal and HTB were approximately dose proportional over the 300-900 mg dose range. In the steady state, the accumulation index (R) indicated that the exposure of triflusal increased slightly with repeated dosing, and the exposure of HTB increased obviously. 3 adverse events certainly related to the investigational drugs occurred in the multiple-dose phase.Following oral dosing under fasting condition, triflusal is promptly absorbed and rapidly depleted from the systemic circulation. HTB is quickly generated from triflusal and slowly eliminated. Triflusal accumulates slightly in the body. HTB plasma concentration builds up progressively toward steady-state.

Topics: Adult; Area Under Curve; Asian People; Female; Healthy Volunteers; Humans; Male; Salicylates; Young Adult

The mean follow-up in the clinical trials of antiplatelet drugs in the secondary prevention of ischemic atherothrombotic stroke ranges from 1 to 5.5 years. Thus, the safety and efficacy of these drugs in the very long term is not totally documented. We have assessed the safety and effectiveness of triflusal and aspirin for a very long-term period in the secondary prevention of patients with ischemic atherothrombotic stroke.. Patients with atherothrombotic ischemic stroke, including TIA, who participated in randomized clinical trials of triflusal versus aspirin were included in the study. The period of recruitment was between 1983 and 1999. After finishing their participation in the clinical trials, patients were followed up in the Neurology Department of our hospital. All patients were treated with aspirin or triflusal during a mean period of 17.2 years. Groups were comparable with respect to sex, age, risk factor and etiology of the stroke. Adverse events and vascular events (including stroke recurrence, ischemic heart disease and vascular death) that appeared throughout the study were registered. Statistical analysis was performed using the statistical package SPSS 15.0 for Windows. Kaplan-Meier curves and the log-rank test were used to compare treatments.. A total of 441 patients (305 men) with a mean age (±SD) of 51.1±12.4 years were included in the study; 288 patients (65.3%) were treated with triflusal and 153 with aspirin. There were no statistically significant differences between aspirin and triflusal concerning new vascular events (72.5 vs. 60.4%; p=0.28), stroke recurrence (49.7 vs. 46.5%; p=0.53), ischemic heart events (54.9 vs. 55.6%; p=0.90), vascular death (25.5 vs. 24%; p=0.73) and global mortality (42.5 vs. 42%; p=0.92). The incidence of serious bleeding (upper digestive tract hemorrhage and cerebral hemorrhage) was 18.3% in aspirin-treated patients and 5.5% in triflusal-treated patients (p<0.001). In reference to other adverse events, no significant differences were found between aspirin and triflusal.. In the secondary prevention of ischemic stroke, very long-term treatment with triflusal or aspirin seems to have a similar efficacy, but triflusal is safer with a lower hemorrhagic risk. Triflusal may be an alternative therapy, particularly in patients who present aspirin resistance.

Topics: Aged; Aspirin; Brain Ischemia; Dyspepsia; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Intracranial Arteriosclerosis; Ischemic Attack, Transient; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Secondary Prevention; Vascular Diseases

Triflusal is a drug that inhibits platelet aggregation. In this study we investigated the dose-exposure-response relationship of a triflusal formulation by population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of its main active metabolite, hydroxy-4-(trifluoromethyl) benzoic acid (HTB).. This study was a randomized, open-label, multiple-dose, two-period, two-treatment, comparative crossover design. All volunteers received a single oral loading dose of 900 mg of triflusal on Day 1, followed by a dose of 600 mg/day from Day 2 to 9. Using data from 34 healthy volunteers, 476 HTB plasma concentration data points and 340 platelet aggregation data points were used to construct PK and PD models respectively using NONMEM (version 6.2). As the PD endpoint was qualitative, we implemented binary analysis of 'inhibition' and 'non-inhibition' rather than using the actual value of the test. The final PK-PD model was evaluated using a visual predictive check (VPC) and bootstrap.. The time-concentration profile of HTB over the entire dosing period was described by a one-compartment model with a first-order formation rate constant for HTB. Weight was selected as a covariate for clearance and volume of triflusal, respectively. The structure and the population estimates for triflusal PK were as follows: oral clearance (CL/F) = 0.2 · (weight/71.65)(0.845) L/h, oral volume of distribution (V/F) = 8.3 · (weight/71.65) L, and k f  = 0.341 h(-1). A sigmoid relationship between triflusal concentration and the probability of significant inhibition with shape factor was chosen as the final PD model. No time delay between concentration and response was identified. The final structure between predicted concentration (C(y)(pred,ij) and the probability of inhibition of platelet aggregation (IPA) relationship was as follows: Probability of IPA = C(19)(pred,ij)/((84.9)(19) µg/mL + C(19)(pred,ij)). Thus, we concluded this relationship is more like quantal concentration-response relationship. The current dosing regimen was considered to be efficacious based on the EC 50 estimate of 84.9 μg/mL obtained in this study.. A PK and binary probability PD model of triflusal was successfully developed for Korean healthy volunteers. The model may be used to further prediction inhibition of platelet aggregation by triflusal.. Clinical Research Information Service (CRIS), KCT0001299 (Registered December 5, 2014).

Topics: Adult; Cross-Over Studies; Healthy Volunteers; Humans; Male; Middle Aged; Models, Theoretical; Platelet Aggregation Inhibitors; Republic of Korea; Salicylates; Young Adult

Although drug-eluting stents have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures, some adverse effects, such as late stent thrombosis, have been described. We evaluated clinical performance of paclitaxel-eluting stents coated with a new bioactive polymer system (P-5) based on a copolymer of an acrylic derivative of triflusal in patients with coronary artery disease.. This was a multicenter, observational, prospective study to assess the incidence of target lesion revascularization (TLR) at 6 months and clinical major adverse cardiac events (MACEs) at 1 and 6 months and 1 and 2 years post-stent implantation in 537 patients. After stent implantation, only 1 case of thrombus and acute occlusion was reported in 1 lesion (0.14%). The incidence of new TLR was 0.89% at 6 months, 1.08% at 1 year, and 1.49% at 2 years, with a cumulative incidence of 3.54%. MACEs included cardiac death (0.93%), myocardial infarction (0.37%), and cardiac surgery (0.19%). No cases of late or very late stent thrombosis were recorded.. Under routine clinical practice, the implantation of paclitaxel-eluting stents coated with P-5 is associated with favorable clinical outcomes in both the short and long term (2 years) in patients with coronary artery disease.

Topics: Aged; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Incidence; Male; Middle Aged; Paclitaxel; Percutaneous Coronary Intervention; Polymers; Prospective Studies; Registries; Salicylates; Thrombosis; Treatment Outcome

Triflusal is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. It was initially marketed as capsules containing 300 mg of active substance. In 2006 a new 600 mg (10 ml) oral solution form of triflusal was authorized in Spain. The primary aim of this study was to compare the gastrointestinal safety of the new triflusal oral solution with triflusal capsules in healthy volunteers.. Sixty healthy subjects were randomly assigned, in a 2.5:2.5: 1 ratio, into one of three groups, with 25 subjects receiving one bottle of triflusal oral solution (600 mg) daily, 25 subjects receiving two triflusal capsules (600 mg) once daily, and ten subjects receiving two placebo capsules once daily, respectively, during 7 consecutive days. Gastroscopy was performed at baseline before the administration of study drugs and after 4-8 h of the last dose of study drugs. Effects on the esophagus, stomach, and duodenum were measured in accordance with a modified Lanza scale.. No differences between groups were detected at baseline. After treatment, median global scores in the placebo, triflusal solution, and triflusal capsules groups were, respectively, 0, 1, and 3 (p = 0.003 for comparison between placebo and triflusal capsules and p = 0.042 for comparison between triflusal solution and triflusal capsules). There were no significant differences between the scores on the triflusal solution and placebo groups. All treatments were well tolerated.. In healthy subjects, triflusal solution induced less endoscopically apparent gastrointestinal mucosal damage than triflusal capsules and did not induce more damage than the placebo in healthy volunteers.

Topics: Administration, Oral; Adult; Capsules; Double-Blind Method; Endoscopy, Gastrointestinal; Female; Gastric Mucosa; Gastrointestinal Tract; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Spain; Statistics as Topic; Therapeutic Equivalency; Young Adult

An enteric-coated formulation of triflusal (triflusal EC), an antiplatelet agent, was developed to reduce the high incidence of gastrointestinal adverse events (AEs). The aim of this study is to compare the pharmacokinetics, pharmacodynamics and safety of triflusal EC with triflusal in healthy Korean male subjects to determine bioequivalence and non-inferiority for the purposes of marketing approval.. A randomized, open-label, two-period, crossover study was conducted in 38 subjects. Either triflusal EC or triflusal was administered orally as a single 900 mg loading dose (day 1) followed by eight 600 mg/day maintenance doses on days 2 - 9, with a 13-day washout period. The plasma concentrations of 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), the predominant active metabolite of triflusal, were assessed after administration of the loading dose, using HPLC/MS/MS. The platelet aggregation response to arachidonic acid was determined using turbidimetric aggregometry.. The 90% CIs, for the geometric mean ratios of the log-transformed AUC(τ) and C(max) of HTB were seen to be within the predetermined range of 0.8 - 1.25. Triflusal EC was also shown to be non-inferior in its anti-aggregatory effect. No serious AEs were reported during this study.. The pharmacokinetic and pharmacodynamic profiles of the two triflusal formulations met the requirements for bioequivalence and non-inferiority, respectively. Both formulations were well tolerated.

Topics: Administration, Oral; Adult; Arachidonic Acid; Asian People; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cross-Over Studies; Dose-Response Relationship, Drug; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Tandem Mass Spectrometry; Therapeutic Equivalency; Young Adult

Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulati

Topics: Adult; Area Under Curve; Biological Availability; Capsules; Chemistry, Pharmaceutical; Cross-Over Studies; Double-Blind Method; Female; Half-Life; Humans; Male; Pharmaceutical Solutions; Platelet Aggregation Inhibitors; Salicylates; Young Adult

Triflusal is a 4-fluoromethyl derivative of salicylic acid used for secondary prevention of ischemic stroke. Recent experimental data (permanent middle cerebral artery occlusion in rats) have shown a possible role of triflusal in neuroprotection through inhibition of inflammatory pathways.. To explore whether triflusal may modulate those pathways in human stroke, evolution of several inflammation markers (pro-inflammatory, adhesion molecules, chemokines, metalloproteinases, apoptosis and angiogenesis-related biomarkers) and neurological outcome were evaluated at baseline, and at days 1, 3, 7 and 90 in a pilot study in which 30 patients with acute ischemic stroke were randomly allocated to receive triflusal or aspirin.. An increase in IL-6 level was found in the aspirin group when compared to the triflusal group at the third and seventh day (p < 0.05). FGF-basic level was significantly increased at days 1 and 90 in the triflusal group (p = 0.040). The triflusal group also had higher levels of MIP-1alpha and MIP-1beta (p < 0.05) at day 1. Also among triflusal-treated patients, MCP-1 and TARC levels were increased as compared with the aspirin group at day 90 (p < 0.05). Interestingly, some of those markers modified by triflusal (MCP-1 and IL-6) were associated with neurological outcome: higher MCP-1 measured at day 3 among patients who improve at day 7 [462.3 (419.2-735.2) vs. 285 (242.1-428.2), p < 0.05], and lower levels of IL-6 at day 3 among patients who improve at day 90 [24.8 (5.6-77.3) vs. 5.4 (2.0-13.8), p < 0.05].. Triflusal modulates additional mechanisms to those of aspirin [pro-inflammatory (IL-6) and chemokine (MIP-1 and MCP-1) pathways] that could participate in the ischemic damage process following human acute stroke.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Aspirin; Biomarkers; Brain Ischemia; Female; Humans; Inflammation Mediators; Logistic Models; Male; Middle Aged; Neuroprotective Agents; Pilot Projects; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates; Stroke; Time Factors; Treatment Outcome

Triflusal is a derivative of acetylsalicylic acid but it exhibits different pharmacological and pharmacokinetic properties. The object of this study was to evaluate the efficacy of additional use of triflusal in patients who underwent drug-eluting stent implantation. First, we prospectively tested platelet function with a rapid platelet function analyzer (VerifyNow-Aspirin) in patients with stable angina (male, age, 61.6 +/- 8.3, body weight, 69.3 +/- 11.2 kg) who maintained dual (aspirin 100 mg and clopidogrel 75 mg per day, n = 23) or triple (aspirin 100 mg, clopidogrel 75 mg, and triflusal 300 mg per day, n = 23) therapy for more than one month. They were randomly assigned to a group. The triple group showed superior inhibition of arachidonic acid induced platelet aggregation compared to the dual group (420.2 +/- 47.7 ARU versus 465.0 +/- 71.2 ARU, P = 0.016). Second, we compared composite outcomes (death, myocardial infarction, and nonhemorrhagic stroke) after drug-eluting stent (DES) implantation between the dual (n = 1474) and triple (n = 433) groups in the prospective Seoul National University Hospital drug-eluting stent (SNUH-DES) cohort. The triple group had more current smokers, male patients, and patients with a previous history of revascularization. Also, the triple group underwent more complex interventions such as left main, chronic total occlusion, long lesion, and restenotic lesion than the dual group. In spite of their higher risk profiles, the triple group patients showed comparable composite outcomes (19 cases, 4.4%) to those of the dual group ones (41 cases, 2.8%) (P = 0.12). The triflusal-based triple antiplatelet therapy achieved superior platelet inhibition compared to the dual therapy ex vivo and it could be applied after complex intervention with DES.

Topics: Drug Combinations; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Penile Implantation; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates

Triflusal (CAS 322-79-2) is an antiplatelet agent related to salicylates used in several European and Latin American countries in the treatment of cardiovascular diseases. The aim of this paper was to evaluate the bioequivalence of triflusal derived from two preparations using both parent drug and metabolite pharmacokinetic data. The bioavailabolity was measured in 24 healthy male Caucasian volunteers following a single oral dose (600 mg) of the test or reference products in the fasting state. Blood samples were collected for 120 h. Plasma concentrations of triflusal and its metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) were analyzed by high-performance liquid chromatography with UV and fluorescence detection, respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax, AUC0-t and AUC0-infinity were tested for bioequivalence using ANOVA and Schuirmann's two-one sided t-test. Tmax was analyzed by nonparametric pharmacokinetic parameters of triflusal and HTB derived from the two formulations were nearly consistent with previous observations. Triflusal parameters derived from the test and reference drug were as follows: Cmax (16.85 +/- 11.41 vs 14.48 +/- 7.22 mg/l), AUC0-t (18.43 +/- 10.91 vs 16.22 +/- 7.58 mg/l per hour), Tmax (1 range 0.25-2h vs 0.875 range 0.25-1.5 h), and t(1/2) (0.49 +/- 00.27 vs 0.76 +/- 0.64). HTB parameters after test and reference formulation administration were as follows: Cmax (68.13 +/- 23.05 vs 65.51 +/- 19.44 mg/l), AUC0-t (2748.18 +/- 971.91 vs 2877.97 +/- 881.2 h x mg/l), AUC0-infinity (3350.15 +/- 1182.62 vs 3372.49 +/- 1110.35 h x mg/l), Tmax (2 range 1-10 h vs 2 range 0.75-12 h), and t(1/2) (42.19 +/- 7.82 vs 43.13 +/- 6.56 h). 90% of confidence intervals for the test/reference ratio of Cmax AUC0-t and AUC0-infinity derived from both triflusal and HTB were found within the range of 80%-125% acceptable for bioequivalence. No significant difference was found between the Tmax values for triflusal and HTB. It was concluded that the two preparations are bioequivalent and may be prescribed interchangeably.

Topics: Adolescent; Adult; Area Under Curve; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Platelet Aggregation Inhibitors; Reference Standards; Salicylates; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Therapeutic Equivalency

Aspirin, a cyclo-oxygenase (COX)-1 and COX-2 inhibitor, is the antiplatelet drug of choice to prevent serious vascular events. Adverse reactions to aspirin are frequent particularly among patients with asthma, chronic rhinosinusitis and nasal polyps. COX-1 inhibitors but not COX-2 inhibitors precipitate asthma attacks. Triflusal is a preferential COX-2 inhibitor antiplatelet agent that is as effective as aspirin in the prevention of serious vascular events. The aim of the study was to assess the tolerability of triflusal in patients with aspirin-exacerbated respiratory disease (AERD).. We studied 26 asthma patients [11 males, aged 52 (23-75) years] who had suffered asthma episodes triggered by one or more (23% of patients) nonsteroidal anti-inflammatory drugs. Aspirin sensitivity was confirmed by either intranasal or oral aspirin challenge. All subjects underwent a single-blind, placebo-controlled oral challenge with three doses of triflusal separated by 1 week (first cumulative dose = 225 mg; second cumulative dose = 450 mg; third cumulative dose = 900 mg). Cutaneous, respiratory, general symptoms and lung function were monitored for 4 h in the laboratory and for 24 h at home.. No clinical reactions to triflusal were observed. There were no significant changes in lung function measurements.. Our study appears to demonstrate that triflusal is a suitable alternative to aspirin as antiplatelet agent to prevent AERD.

Topics: Administration, Oral; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Probability; Reference Values; Respiratory Function Tests; Risk Assessment; Salicylates; Severity of Illness Index; Single-Blind Method; Treatment Outcome

Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported.. The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion.. This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects.. Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans.. The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release.. The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.

Topics: Aged; C-Reactive Protein; Calcium; Cross-Over Studies; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Salicylates

Triflusal has been shown to exert neuroprotective effects by downregulating molecules considered responsible for the development of Alzheimer's disease (AD). The aim of this study was to develop a population pharmacokinetic model to characterize plasma and cerebrospinal fluid (CSF) pharmacokinetics of the main active metabolite of triflusal-HTB (2-hydroxy-4-trifluoro-methylbenzoic acid)-in healthy volunteers.. Data from two studies were combined. Study A: subjects received single oral doses of triflusal 900 mg. Triflusal and HTB plasma concentrations were extensively measured. Study B: triflusal 600 mg once daily was administered orally for 14 days. HTB plasma and CSF concentrations were determined in healthy volunteers. Population pharmacokinetic modeling was performed using NONMEM.. A one-compartmental model with rapid first-order absorption for triflusal and first-order formation of HTB best described plasma concentrations. Triflusal elimination rate constant was 50 times faster than that estimated for the metabolite. CSF concentrations of HTB ranged between 0.011 microg/ml and 0.341 microg/ml. A CSF-plasma partition coefficient of 0.002 and a k(e0) value of 0.059 h(-1) were estimated by means of population modeling.. In the present study in healthy volunteers, HTB penetrated into the CSF in a range of concentrations experimentally proven to have protective effects in AD. These concentrations suggest that triflusal could be used in the treatment of central nervous system diseases in doses similar to those used in cardiovascular diseases. Access to the CSF compartment was characterized by a slow equilibrium rate constant and a low CSF-plasma partition coefficient.

Topics: Adult; Blood-Brain Barrier; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Female; Humans; Male; Metabolic Clearance Rate; Models, Biological; Neuroprotective Agents; Salicylates

Antiplatelet agents are used for prevention of thromboembolism in surgical patients and in patients with chronic atrial fibrillation. Up to date, however, results of randomized studies comparing antiplatelet agents and oral anticoagulation have not been reported. The aim of this study was to compare the efficacy and safety of triflusal (an antiplatelet agent) versus acenocoumarol for primary prevention of thromboembolism in the early postoperative period after implantation of a bioprosthesis.. In this prospective, multicentric, randomized, open pilot trial, patients were assigned to treatment with triflusal (600mg/d) or acenocoumarol (target INR 2.0-3.0). Study medication was started 24-48h after valve replacement with a bioprosthesis, and continued for 3 months. Four follow-up visits were scheduled: baseline, and at 1, 3 and 6 months thereafter. The primary end-point was a composite of the rate of thromboembolism, severe hemorrhage and valve-related mortality.. A total of 193 patients were included (97 received triflusal and 96 acenocoumarol), with a mean age of 72.5 years. Half were men. Aortic valve replacement was performed in 181 patients (93.8%), mitral valve replacement in 10 patients (5.2%) and double valve replacement in 2 (1.0%). Hospital mortality was 11 (5.7%). Primary outcome was recorded in 9 patients with triflusal (9.4%) and in 10 patients with acenocoumarol (11%). There were nine episodes (4.7%) of thromboembolism, six in the triflusal group and three in the acenocoumarol group, and three episodes of permanent neurological deficits, one in the triflusal group and two in the acenocoumarol group. Severe hemorrhage: nine episodes, six in the acenocoumarol group and three in the triflusal group. None of the observed differences in efficacy were statistically significant. Regarding safety, three patients in triflusal group reported at least one hemorrhage, compared to 10 in acenocoumarol group (P=0.048).. There were no significant differences in efficacy between both groups, however, triflusal showed a significantly lower incidence of bleeding episodes.

Topics: Acenocoumarol; Aged; Anticoagulants; Bioprosthesis; Epidemiologic Methods; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Male; Platelet Aggregation Inhibitors; Postoperative Complications; Postoperative Hemorrhage; Salicylates; Thromboembolism

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.

Topics: Adult; Aged; Aspirin; Biomarkers; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation Inhibitors; Radioimmunoassay; Retrospective Studies; Salicylates; Thromboxane B2; von Willebrand Factor

Triflusal is an antiplatelet agent that has shown clinical advantages when compared with aspirin in the secondary prevention of vascular events. TAPIRSS (Triflusal versus Aspirin for Prevention of Infarction: a Randomized Stroke Study) explored the efficacy and safety of triflusal in the secondary prevention of stroke in a Latin American homogeneous population with the ultimate aim of preparing for a larger trial in the same setting.. A double-blind, multicenter, randomized, pilot trial was conducted in Buenos Aires, Argentina, from October 1996 to November 1999. The study sample was 431 patients, randomized to receive aspirin 325 mg daily or triflusal 600 mg daily for a mean of 586 days. All patients had experienced either an ischemic stroke or TIA within 6 months from enrollment. Data from 429 patients were analyzed.. No differences were observed in the primary endpoint that combined the incidence of vascular death, cerebral ischemic infarction, nonfatal myocardial infarction, or major hemorrhage (aspirin 13.9%, triflusal 12.7%; odds ratio [OR] 1.11, 95% CI 0.64 to 1.94) or in the individual analysis of each component of the primary endpoint. In a post hoc analysis, the overall incidence of major and minor hemorrhagic events was significantly lower in triflusal-treated patients (aspirin 8.3%, triflusal 2.8%; OR 3.13, 95% CI 1.22 to 8.06).. This pilot trial has not found differences between triflusal and aspirin in the prevention of vascular complications after TIA or ischemic stroke, although given the wide CI, potentially important group differences could not be ruled out. Triflusal may be associated with a lower risk of hemorrhagic complications. A larger, prospective clinical trial is necessary to verify these results.

Topics: Aged; Aspirin; Cerebral Infarction; Double-Blind Method; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Odds Ratio; Pilot Projects; Platelet Aggregation Inhibitors; Salicylates; Secondary Prevention; Stroke; Survival Analysis; Treatment Outcome

This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis.. Warfarin was more effective than aspirin in preventing stroke in these patients; combined therapy with low anticoagulant intensity was ineffective. Mitral stenosis patients were not investigated.. We performed a multicenter randomized trial in 1,209 patients at risk. The intermediate-risk group included patients with risk factors or age >60 years: 242 received the cyclooxygenase inhibitor triflusal, 237 received acenocumarol, and 235 received a combination of both. The high-risk group included patients with prior embolism or mitral stenosis: 259 received anticoagulants and 236 received the combined therapy. Median follow-up was 2.76 years. Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism.. Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- (hazard ratio [HR] 0.33 [95% confidence interval (CI)0.12 to 0.91]; p = 0.02) and the high-risk group (HR 0.51 [95% CI 0.27 to 0.96]; p = 0.03). Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group. Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy.. The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Cause of Death; Dose-Response Relationship, Drug; Drug Therapy, Combination; Embolism; Female; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Intracranial Embolism; Male; Middle Aged; Mitral Valve Stenosis; Platelet Aggregation Inhibitors; Proportional Hazards Models; Salicylates; Survival Analysis; Treatment Outcome

The efficacy of the antiplatelet agent triflusal for prevention of vascular events after stroke has been reported in a pilot study. However, there is a need to confirm those results in a larger study.. We performed a randomized, double-blind, multicenter study to test the efficacy of triflusal (600 mg/d) versus aspirin (325 mg/d) for prevention of vascular events in patients with stroke or transient ischemic attack (Triflusal versus Aspirin in Cerebral Infarction Prevention [TACIP]). We assessed a combined end point (incidence of nonfatal ischemic stroke, nonfatal acute myocardial infarction, or vascular death) as well as the incidence of these events separately and the incidence of major hemorrhage.. Of 2113 patients, 1058 received triflusal and 1055 aspirin. The mean follow-up period was 30.1 months. The incidence of combined end point (13.1% for triflusal, 12.4% for aspirin) as well the survival analysis (hazard ratio [HR] for triflusal versus aspirin, 1.09; 95% CI, 0.85 to 1.38) showed no differences between groups. The incidence of nonfatal stroke (HR, 1.09; 95% CI, 0.82 to 1.44), nonfatal acute myocardial infarction (HR, 0.95; 95% CI, 0.46 to 1.98,) and vascular death (HR, 1.22; 95% CI, 0.75 to 1.96) was also similar. A significantly higher incidence of major hemorrhages in the aspirin group was recorded (HR, 0.48; 95% CI, 0.28 to 0.82). The overall incidence of hemorrhage was significantly lower in the triflusal group (16.7% versus 25.2%) (odds ratio, 0.76; 95% CI, 0.67 to 0.86; P<0.001).. This study failed to show significantly superior efficacy of triflusal over aspirin in the long-term prevention of vascular events after stroke, but triflusal was associated with a significantly lower rate of hemorrhagic complications.

Topics: Aspirin; Cardiovascular Diseases; Cerebral Infarction; Double-Blind Method; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Salicylates; Secondary Prevention; Stroke; Survival Analysis

Few trials have studied platelet activity during oral anticoagulation and all show a tendency for platelet aggregation to increase. This adverse effect has also been shown in some patients treated with unfractionated heparin, the so-called white clot syndrome. We studied platelet aggregation in patients with atrial fibrillation enrolled in the NASPEAF study and receiving antiaggregant, anticoagulant and both treatments.. 15 healthy control subjects (group C) and 99 patients were enrolled, the latter receiving 4 different antithrombotic regimens for platelet aggregation: group 1, 600 mg of the antiplatelet drug triflusal; group 2, anticoagulation for an INR of 2-3; and both treatments with 2 different levels of anticoagulation, mean INR of 1.85 (group 3) and of 2.15 (group 4). The same amounts of the agonists ADP, arachidonic acid and collagen were used in all tests. For statistical analysis we used the interval in min, from the addition of the agonist to the beginning of aggregation and the % of aggregation at 5 and 8 min.. After arachidonic acid was given, the interval to the beginning of aggregation was shorter in group 2 than in group C: 0.6 +/- 0.21 and 1.1 +/- 1.2, and in both was significantly shorter than in the other three receiving antiplatelet drugs alone: group 1 = 1.58 +/- 1.4 or combined with anticoagulants: group 3 = 1.7 +/- 1.7 and group 4 = 2.4 +/- 2.1. The % of aggregation at 5 min, in groups C, 2, 1, 3 and 4 was respectively 48 +/- 24, 43.2 +/- 19, 29.6 +/- 17, 34.8 +/- 22 and 23.2 +/- 22.5. The data showed significantly increased platelet activity in groups C and 2 compared to groups 1, 3 and 4. Group 3 with a low anticoagulation level (mean INR = 1.85) showed a tendency to greater platelet activity than group 1 and 4 with p value = 0.08.. The antiplatelet drug triflusal alone or combined with a therapeutic level of anticoagulation effectively reduces platelet aggregation and is not influenced by anticoagulant treatment. A low level of anticoagulation (INR < 2) shows a tendency to increase platelet activity.

Topics: Acenocoumarol; Adenosine Diphosphate; Aged; Analysis of Variance; Anticoagulants; Arachidonic Acid; Atrial Fibrillation; Blood Platelets; Collagen; Embolism; Female; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Time Factors

To compare the costs to the Spanish healthcare system of 35 days' treatment with triflusal (600 mg/day) and aspirin (300 mg/day) in patients with confirmed acute myocardial infarction within 24 hours of onset of symptoms.. A cost minimisation analysis based on the results of the Triflusal in Acute Myocardial Infarction study (TIM) was conducted. The hypothesis was that despite a higher acquisition cost of triflusal, savings would result because of differences in efficacy and safety outcome (non-fatal cerebrovascular event and haemorrhagic events). Diagnostic Related Groups were used as a proxy for determining hospital costs in Spain and the values were obtained from different sources and refer to year 2000 costs. Only direct medical costs were considered for the economic analysis.. Although the acquisition cost of triflusal was more expensive than that of aspirin, the cost of prevented events - non-fatal ischaemic cerebrovascular events and cerebral haemorrhages - entirely compensated for the cost of triflusal. The overall cost of treating patients with triflusal, compared with aspirin, represented a net saving of 28.4% per patient treated.. Our study showed that triflusal is cost saving compared with aspirin in the treatment of the acute phase of myocardial infarction.

Topics: Acute Disease; Aspirin; Double-Blind Method; Drug Costs; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Spain

To compare the efficacy and tolerability of the antiplatelet agent triflusal with aspirin in the prevention of cardiovascular events following acute myocardial infarction.. In this double-blind, multicentre, sequential design study, patients were randomized within 24 h of acute myocardial infarction symptom onset to receive triflusal 600 mg or aspirin 300 mg once daily for 35 days. The primary end-point was death, non-fatal myocardial reinfarction or a non-fatal cerebrovascular event. The incidences of these individual outcomes and urgent revascularization were secondary end-points. The null hypothesis of no difference between treatments in the primary combined end-point was accepted with 80% power after recruiting 2124 validated patients (odds ratio (OR) for failure [95% confidence interval (CI)]: 0.882 [0.634-1.227]). Non-fatal cerebrovascular events were significantly less frequent with triflusal (OR [95% CI]: 0.364 [0.146-0.908]; P = 0.030). There was no significant difference between treatments for death (OR [95% CI]: 0.816 [0.564-1.179]; P = 0.278), non-fatal reinfarction (OR [95% CI]: 1.577 [0.873-2.848]; P = 0.131) or revascularization (OR [95% CI]: 0.864 [0.644-1.161]; P = 0.334). Overall, both drugs were well tolerated, although there was a trend towards fewer bleeding episodes with triflusal; significantly fewer central nervous system bleeding episodes were observed in triflusal-treated patients (0.27% vs. 0.97%; P = 0.033).. Triflusal and aspirin have similar efficacy in preventing further cardiovascular events after acute myocardial infarction, but triflusal showed a more favourable safety profile. Triflusal significantly reduced the incidence of non-fatal cerebrovascular events compared with aspirin.

Topics: Aged; Aspirin; Cerebrovascular Disorders; Double-Blind Method; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Spain; Treatment Outcome

The aim of the study was to investigate the effects of the antiplatelet agent triflusal on the changes in platelet function in patients who underwent a cardiopulmonary bypass for coronary arteries (CABG). In 20 surgical patients, blood was sampled before and at the conclusion of surgery, 48 h later (in the intensive care unit), and after 10 days of treatment with 600 mg/day triflusal (triflusal was administered from the first day after surgery). Adenosine diphosphate (ADP) and collagen-induced platelet aggregation in whole blood, granular release of beta-thromboglobulin and platelet release of thromboxane B2 were measured. Basal values were compared with results in a group of ten healthy volunteers. All platelet determinations of activation were higher in coronary patients than in healthy volunteers. Immediately after CABG, the platelet reactivity to ADP and collagen were significantly lower, and release of beta-thromboglobulin and thromboxane B2 were higher, than in the pre-CABG samples. During the patient's stay in the intensive care unit, all values tend to return to pre-CABG values. Triflusal inhibits both platelet beta-thromboglobulin (63% with respect to the post-CABG value) and thromboxane B2 (91% with respect to the post-CABG value) release. Platelet aggregation after 10 days of triflusal treatment tended to return to the pre-CABG values. In conclusion, Triflusal reduces platelet activation caused by the coronary artery bypass graft surgery.

Topics: Adenosine Diphosphate; Adult; Aged; beta-Thromboglobulin; Collagen; Coronary Artery Bypass; Erythrocyte Count; Female; Hematocrit; Hemoglobins; Humans; Leukocyte Count; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Salicylates; Thromboxane B2; Time Factors

The thrombotic process is a multicellular phenomenon in which not only platelets but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal, a 4-trifluoromethyl derivative of salicylate, reduced platelet aggregation not only by inhibiting thromboxane A2 production but also by stimulating nitric oxide (NO) generation by neutrophils. The aim of the present study was to evaluate whether oral treatment of healthy volunteers with triflusal could modify the ability of their neutrophils to produce NO and to test the role of the NO released by neutrophils in the modulation of ADP-induced platelet aggregation and alpha-granule secretion.. The study was performed in 12 healthy volunteers who were orally treated with triflusal (600 mg day-1) for 5 days. Flow cytometric detection of platelet surface expression of P-selectin was used as a measure of the ability of platelets to release the contents of their alpha-granules.. After treatment with triflusal, there was an increase in NO production by neutrophils and an increase in endothelial nitric oxide synthase (eNOS) protein expression in neutrophils. A potentiation of the inhibition of platelet aggregation by neutrophils was reversed by incubating neutrophils with both an L-arginine antagonist, NG-nitro-L-arginine methyl ester (L-NAME) and an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline 1-oxyl 3-oxide (C-PTIO). A slight decrease in P-selectin surface expression on platelets was found which was not modified by the presence of neutrophils and therefore by the neutrophil-derived NO. Exogenous NO released by sodium nitroprusside dose-dependently inhibited both ADP-stimulated alpha-granule secretion and platelet aggregation. Therefore, platelet aggregation showed a greater sensitivity to be inhibited by exogenous NO than P-selectin expression.. Oral treatment of healthy volunteers with triflusal stimulated NO production and eNOS protein expression in their neutrophils. After triflusal treatment, the neutrophils demonstrated a higher ability to prevent ADP-induced platelet aggregation. However, the neutrophils and the endogenous NO generated by them failed to modify P-selectin expression in ADP-activated platelets.

Topics: Administration, Oral; Adult; Humans; Male; Neutrophils; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates

In order to evaluate the effect of triflusal (2-acetyloxy-4-trifluoromethyl benzoic acid), an orally active antiplatelet agent, on arteriosclerosis progression, a pilot, parallel, double-dummy, double-blind clinical trial vs acetylsalicylic acid (ASA) was carried out in patients with subclinical atherosclerotic lesions. The trial consisted of a 2-week run-in placebo phase, followed by a 12-month oral treatment with triflusal (600 mg/day) or ASA (300 mg/day). The primary variable was identified in the ultrasonic biopsy (UB) score; the secondary variables were the UB class changes of each arterial site, the rate of progression (ROP), the intima-media thickness (IMT), and the symptoms of arteriosclerosis. Data were evaluated by use of analysis of variance and Chi-square test. Forty-three patients (31 men, 12 women, mean age 62.8 +/- 8.4 SD) were randomized to triflusal (15 men, 6 women, mean age 64.3 +/- 6.7) or to ASA (16 men, 6 women, mean age 61.3 +/- 9.6). The analysis of variance on the UB score showed no difference between treatments: the patients' UB scores remained unchanged with no progression, thus indicating that no patient worsened during treatment. When all arterial sites under evaluation are considered, 86% of the sites in the triflusal group and 85% in the ASA group remained unchanged. No relevant change was recorded in vital signs and routine laboratory tests. Gastric disturbances were reported by two and three patients treated with triflusal and ASA, respectively. In conclusion, triflusal appears as effective as ASA in slowing arteriosclerosis progression.

Topics: Administration, Oral; Adult; Aged; Analysis of Variance; Arteriosclerosis; Aspirin; Carotid Artery Diseases; Chi-Square Distribution; Disease Progression; Double-Blind Method; Female; Femoral Artery; Humans; Male; Middle Aged; Pilot Projects; Placebos; Platelet Aggregation Inhibitors; Salicylates; Stomach; Tunica Intima; Tunica Media; Ultrasonography

Vascular dementia is the second commonest cause of dementia after Alzheimer's disease. The most important risk factor for this is previous cerebral vascular accident.. To eliminate the risk factors and/or progression of this illness would be of considerable benefit to these patients. Triflusal, a platelet anti-aggregant chemically related to the salicylates, whose clinical efficacy has been shown in cardiac and cerebrovascular pathology, has been used in the treatment of patients with vascular dementia.. An open study was done a sample of 73 patients with vascular dementia randomly distributed into two groups (control and undergoing treatment with triflusal).. To check the efficacy of treatment with triflusal, the percentage of variation in the scoring of the Cognitive Mini Examination was used after a clinical course of 12 months (IVP 12), considering the critical point of no efficacy to be a loss equal or greater than 10%. In the control group, 33% (8/24) and in the group treated with triflusal 8% (3/35) had a negative course which was greater than this critical point.. The difference in the IVP 12 between the two groups was statistically significant (p = 0.0375), with a statistical power of 87% (beta = 0.13). This gives triflusal a therapeutic activity which is sufficient to limit cognitive deterioration of patient with vascular dementia.

Topics: Aged; Cerebrovascular Disorders; Dementia, Vascular; Female; Humans; Male; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Factors; Salicylates

The effectiveness of the low doses AAS in the prevention of the cerebral infarction has not been clearly still verified.. To compare the long term effectiveness of the treatment with low doses AAS in front of triflusal in the reduction of the stroke, ischemic cardiopathy, and cardiovascular death risks.. Of 386 patients with a first ischemic stroke, 217 were selected (106 triflusal, 111 AAS) that completed the approaches of atheromatous infarct (161 males, 72.2% and 58 female, 25.8%). The mean age was 43 years (standard deviation, SD 6.4, 95% CL 20-50). The patients received one of theses treatments: a) AAS (Sedergine) 330 mg/day (once a day); b) Triflusal (Disgren), 900 mg/day (300 mg 3 times a day). The mean time of follow-up for the group triflusal was of 48.3 months (20-94), while for the group AAS was of 46.3 months (2-84).. The combined incidence of cerebral infarcts, ischemic cardiopathy and vascular death was 19.8% in the patients treated with triflusal, and 28.8% in the patients treated with AAS what supposes a reduction of the risk of the 39% (OR 0.61; CL 0.30-2.01). In the subgroup of patients with carotid stenoses of more than 70% demonstrated by angiography, triflusal produces a significant reduction of risk (OR 0.30; CL 0.10-0.90). Also, triflusal reduced in 76% the risk of hemorrhagic complications in comparison of the AAS (OR 0.24; IC 0.06-0.94).. The study adds new doubts about the effectiveness of the low doses of AAS in the secondary prevention of the cerebral infarct. The triflusal shows effectiveness in subgroup of high risk and a significative reduction of the hemorrhagic complications that would be confirmed in controlled clinical trials with a greater number of patients.

Topics: Adult; Aspirin; Brain Ischemia; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Salicylates; Survival Rate

Pulmonary embolism (PE) is a serious complication following hip surgery. Trials of antiplatelet thromboprophylaxis indicated a substantial reduction in PE rate, and we prospectively studied the effect of a combination of low-dose heparin and two different antiplatelets. Furthermore, our experience in previous studies suggested that platelet count (PC) levels could be useful to reliably suspect PE at a very early stage, and we prospectively tried to confirm our previous findings. Ours is a prospective study in 459 consecutive patients operated on because of hip fracture (265) or elective hip replacement (194), aimed to determine: 1) whether the benefits of antiplatelets plus heparin on PE outweigh the risks; 2) to assess the clinical usefulness of PC monitoring in these patients, so as to confirm whether PE could be recognized early. It was a prospective, randomized, double-blind study. All patients received unfractioned heparin (7500 IU sc twice daily, starting 2 h before operation). In addition, they received aspirin (200 mg thrice daily, with meals), Triflusal (300 mg thrice daily, with meals), or placebo. Real time B-mode ultrasonography (US) was performed on all patients on the 8-9th day after surgery. Venography was performed in patients with normal US, if clinical symptoms suggested venous thrombosis. Twelve out of the 459 patients (2.6%) had to discontinue prophylaxis, because of major bleeding (6 patients), or gastric intolerance (6 patients). There were no significant differences between groups in either deep vein thrombosis (26 patients (18%) with aspirin, 18 (12%) with Triflusal, 26 (17%) with placebo), or PE development (7 patients (5%) with aspirin, 3 (2%) with Triflusal, 8 (5%) taking placebo).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Aged, 80 and over; Aspirin; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Hip Fractures; Hip Prosthesis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Postoperative Complications; Prospective Studies; Pulmonary Embolism; Radionuclide Imaging; Salicylates; Thrombophlebitis; Treatment Outcome; Ultrasonography; Vomiting

Many clinical trials have shown the effectiveness of platelet-antiaggregant drugs in the treatment of obliterative peripheral arteriopathy, both locally and in the system, by improving the claudication symptoms and by preventing major cardiovascular events. In this study we evaluated the effectiveness of a 24-week treatment with triflusal, a comparatively new inhibitor of platelet aggregation, in patients affected by chronic peripheral arteriopathy, comparing twice-daily oral doses of 300 mg triflusal with twice-daily placebo doses. The percentages of successes (defined as a 40% increase of total walking distance over the basal control) were 63.6% in the triflusal group (35/55 patients) and 22.5% in the placebo group (14/62 patients). Patients treated with triflusal showed a more important increase in total walking distance and in pain-free walking distance over the basal values than those treated with placebo, together with an improvement of the symptomatology correlated with claudication. Moreover, in the triflusal group there was an increase in the peak-flow recorded through strain-gauge plethysmography. In conclusion, triflusal significantly increased both the distance which could be walked and the clinical symptoms, presumably by improving microperfusion.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Salicylates

We analyzed the clinical characteristics of the 58 diabetic and 218 nondiabetic patients enrolled in the Spanish multicentre trial of trifusal in unstable angina. After 6 months of follow-up, 25 suffered from myocardial infarction or death, 10 of which were diabetics (17.2%) and 15 nondiabetics (6.9%) (P = 0.0146). This difference remained significant after multivariate analysis. We conclude that diabetes is an independent predictor of adverse outcome in patients with medically treated unstable angina.

Topics: Aged; Angina, Unstable; Diabetes Complications; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Myocardial Revascularization; Platelet Aggregation Inhibitors; Prognosis; Salicylates; Spain; Treatment Outcome

The efficacy and safety of Triflusal capsules given to patients at thrombogenetic risk because of platelet hyperaggregation were investigated in a controlled study involving 15 patients (9 males and 6 females, mean age 65.7 years) who were given 300 mg/day of Triflusal during the first 5 days and 600 mg/day during the following 5 days. Subsequently, after 7 days of wash-out all these patients received placebo for 10 days, one capsule for the first 5 days and 2 capsules for the following 5 days. The platelet antiaggregant activity of the drug was evaluated by means of Born's platelet activation test. Specific tests were also made to assess the effect of this substance on platelet release and the coagulation system. The safety was evaluated by measuring the most important clinical chemistry and clinical haematology indexes of haematopoietic, hepatic, renal and metabolic functions. Arterial blood pressure and heart rate values were also recorded. All the 15 patients completed the study. It was found that the Triflusal treatment led to a significant mean reduction of the indexes chosen as markers of thrombophilia or platelet hyperaggregation in vivo. It did not affect the normal haemostatic-coagulation process and was well tolerated by the patients. The subsequent placebo treatment did not induce any platelet antiaggregant effects.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; beta-Thromboglobulin; Blood Platelet Disorders; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Factor 3; Platelet Factor 4; Salicylates; Thromboxane B2

A multicenter, double-blind, placebo-controlled study was carried out to evaluate the effect of a new antiplatelet agent, triflusal (2-acetoxy-4-trifluoromethyl benzoic acid), in the prevention of nonfatal myocardial infarction and cardiac or vascular death (principal end-points) in patients with unstable angina. 281 patients were randomly assigned to triflusal (300 mg t.i.d.; n = 143) or placebo (n = 138). After 6 months of treatment, the incidence of nonfatal acute myocardial infarction was significantly lower in the triflusal than in the placebo group: 6 patients (4.2%) versus 17 (12.3%), p = 0.013. The low number of deaths (2/143 triflusal versus 0/138 placebo recipients) hampered statistical analysis of mortality rates. The need for revascularization was similar in the two groups: 24 patients (16.8%) in the triflusal group and 28 (20.3%) in the placebo group, p = 0.449. In conclusion, the results show that treatment with triflusal can reduce the incidence of myocardial infarction in patients with unstable angina.

Topics: Administration, Oral; Aged; Angina, Unstable; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Salicylates; Spain; Survival Rate

A randomized, double-blind, placebo-controlled trial was performed in 209 patients to evaluate the efficacy of a low dose of aspirin plus dipyridamole or that of a new antiplatelet agent (triflusal) plus dipyridamole in the prevention of aortocoronary vein-graft occlusion. An angiographic control performed in 161 patients 9 days after surgery showed no significant differences between groups, but a new control on 138 of those patients 6 months later did show significant linear trends towards fewer distal anastomosis occlusions (P = 0.027) from the placebo (24%, 22/91) to the aspirin (16%, 17/106) and to the trifusal groups (12%, 10/86), and towards fewer new occlusions (P = 0.056) from 12% (9/78) to 10% (10/99) and to 2.6% (2/78), respectively, in the same groups. A multivariate logistic regression model, used to determine the effect of 33 variables on distal anastomosis occlusion at 6 months control, demonstrated that diameter of distal bed (P = 0.006), moderately to severely atherosclerotic distal bed (P = 0.003) and the interactions between poor distal bed and triflusal (P = 0.005) were independent predictors of occlusion. Thus, triflusal plus dipyridamole appeared superior to low-dose aspirin plus dipyridamole in the prevention of vein-graft occlusion, independently of coronary and vein-graft determinants of occlusion.

Topics: Adult; Aged; Aspirin; Clinical Trials as Topic; Coronary Artery Bypass; Dipyridamole; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Patient Compliance; Prospective Studies; Random Allocation; Salicylates; Vascular Patency

Ophthalmic evolution was studied for 2 years in 17 patients with insulin-dependent diabetes mellitus and background diabetic retinopathy. Nine patients were treated with triflusal, a new platelet antiaggregant drug, and the eight remaining patients, with similar clinical and biological characteristics, were considered the control group. At the end of the study the ophthalmic evolution was different in the two groups. In the control group the degree of fluorescein leakage and the number of microaneurysms increased, while in the triflusal-treated group both parameters were reduced. There were no differences in visual acuity and computerised perimetry between the groups. Our results suggest that platelet antiaggregant therapy can be useful in the treatment of background diabetic retinopathy.

Topics: Adult; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Humans; Male; Platelet Aggregation Inhibitors; Salicylates; Visual Acuity

Topics: Humans; Photosensitivity Disorders; Salicylates

We sought to investigate stent healing and neointimal hyperplasia with ihtDEStiny drug-eluting stent (DES) by optical coherence tomography (OCT) examination conducted 9 months after implantation.. The currently used DES present certain features that have been linked separately to their better performance in terms of efficacy and safety.. First-in-man, prospective and multicenter study including patients treated with ihtDEStiny stent undergoing OCT examination at 9 months follow up. The ihtDEStiny stent is a sirolimus eluting stent with an oval shape ultrathin struts (68 μm) and an abluminal coating of a fluoropolymer containing the antiplatelet agent triflusal. Primary endpoint was the percentage of obstruction of the in-stent volume by the neointima.. In 58 patients (63 lesions) in-stent late lumen loss was 0.11 ± 0.23 mm (95% CI 0.05-0.16) with only in 6% of stents being > 0.5 mm and in-segment binary stenosis was 1.6%. In OCT mean neointima volume obstruction was 10.5 ± 6.9% with a mean neointima thickness of 110.9 ± 89.8 μm. The proportion of uncovered struts was 2.5%, malapposed struts 1.1% and malapposed/uncovered struts 0.7% and no subclinical thrombi detected. Mean incomplete stent apposition area was 0.1 ± 0.1 mm. In this study the ihtDEStiny stent has shown a very low degree of neointimal proliferation associated with a low rate of uncovered/malapposed struts and total absence of subclinical thrombi at 9 months follow up.

Topics: Coronary Vessels; Drug-Eluting Stents; Humans; Neointima; Percutaneous Coronary Intervention; Prospective Studies; Salicylates; Sirolimus; Stents; Tomography, Optical Coherence; Treatment Outcome

Acetylsalicylic acid hypersensitivity (ASAH) limits therapeutic options in patients with acute coronary syndrome (ACS), who benefit from dual antiplatelet therapy (DAPT), especially when undergoing stent implantation. Our aim was to evaluate the safety and efficacy of triflusal in patients with ACS and ASAH.. Two-center retrospective study of patients diagnosed with ACS and ASAH from January 1, 2000, to May 1, 2020. Sixty-six patients were treated with triflusal. ASAH was confirmed with tests in 15 patients (22.7%). Forty-nine patients (74.2%) presented history of other drug allergies. Fifty-nine patients (89.4%) underwent stent implantation. DAPT was prescribed for ≥12 months in 54 patients. No adverse reactions to triflusal were reported. During a median follow-up of 5.12 years [IQR 2.7-9.9], rate of cardiovascular (CV) mortality was 6.1%, nonfatal myocardial infarction 12.1%, and ischemic stroke 4.5%. No cases of definite stent thrombosis occurred. Bleeding Academic Research Consortium grade ≥2 was observed in 3 patients during follow-up.. In this series of patients presenting with ACS and ASA hypersensitivity, triflusal showed good tolerability and was associated with a low rate of CV and bleeding events.

Topics: Acute Coronary Syndrome; Aspirin; Drug Therapy, Combination; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Retrospective Studies; Salicylates; Treatment Outcome

The antiplatelet effect of low-dose aspirin, via inhibition of cyclooxygenase-1, might contribute to its ability to reduce the risk of colorectal cancer (CRC). Antiplatelet agents with a different mechanism, such as clopidogrel, might have the same effects. We aimed to quantify the effects of low-dose aspirin and clopidogrel on the risk of CRC in a Mediterranean population.. We performed a nested case-control study using a primary care database (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria) in Spain. We collected data, from 2001 through 2014, on 15,491 incident cases of CRC and 60,000 randomly selected individuals (controls), frequency-matched to cases by age, sex, and year. To estimate the association between exposure to different antiplatelet agents and the risk of colorectal cancer, we built multiple logistic regression models and computed the adjusted-odds ratios (AORs) and their respective 95% CIs.. Use of low-dose aspirin was associated with a reduced risk of CRC overall (AOR, 0.83; 95% CI, 0.78-0.89) and in patients receiving treatment for more than 1 year (AOR, 0.79; 95% CI, 0.73-0.85). Use of clopidogrel was associated with a decreased risk of CRC overall (AOR, 0.8; 95% CI, 0.69-0.93) and in patients receiving treatment for more than 1 year (AOR, 0.65; 95% CI, 0.55-0.78). Dual antiplatelet therapy had the same effect as either drug taken as monotherapy. No modification by sex or age was observed.. In a nested case-control study of a primary care database in Spain, we found clopidogrel use, alone or in combination with low-dose aspirin, to reduce the risk of CRC by 20% to 30%, a magnitude similar to that of low-dose aspirin alone. These data support the concept that inhibiting platelets is an effective strategy for prevention of CRC.

Topics: Aged; Aged, 80 and over; Aspirin; Case-Control Studies; Clopidogrel; Colorectal Neoplasms; Dual Anti-Platelet Therapy; Female; Humans; Logistic Models; Male; Middle Aged; Platelet Aggregation Inhibitors; Protective Factors; Risk Reduction Behavior; Salicylates; Spain

Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of FGF20 protects against nigrostriatal tract loss in the 6-hydroxydopamine lesion rat model of Parkinson's disease. Increasing endogenous FGF20 production might provide a less-invasive, more translational way of providing such protection. Accordingly, we adopted a targeted repositioning approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production in brain. In silico interrogation of the Broad Institute's Connectivity Map database (CMap), revealed 50 candidate drugs predicted to increase FGF20 transcription, 16 of which had profiles favourable for use in Parkinson's disease. Of these, 11 drugs were found to significantly elevate FGF20 protein production in MCF-7 cells, between two- and four-fold. Four drugs were selected for examination in vivo. Following oral dosing in rats for 7 days, salbutamol and triflusal, but not dimethadione or trazodone, significantly elevated FGF20 levels in the nigrostriatal tract. Preliminary examination in the unilateral 6-hydroxydopamine-lesioned rat revealed a modest but significant protection against nigral cell loss with both drugs. Our data demonstrate the power of targeted repositioning as a method to identify existing drugs that may combat disease progression in Parkinson's by boosting FGF20 levels.

Topics: Albuterol; Animals; Brain; Computer Simulation; Corpus Striatum; Dimethadione; Dopaminergic Neurons; Drug Repositioning; Female; Fibroblast Growth Factors; Humans; MCF-7 Cells; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Salicylates; Substantia Nigra; Trazodone; Treatment Outcome

Topics: Aged; Aspirin; Drug Hypersensitivity; Female; Fibrinolytic Agents; Graft Occlusion, Vascular; Humans; Male; Myocardial Ischemia; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Salicylates; Stents

The objective of this work is to study the dose-dependent effect of combination therapy with dipyridamole and triflusal over that of triflusal alone on infarct size after middle cerebral artery occlusion (MCAO) ischemia.. Male Wistar rats were subjected to a permanent MCAO in the right hemisphere. Rats received triflusal alone and with dipyridamole via oral route. Three days after surgery, infarct volumes were measured.. The lower dose regime of triflusal (10 mg/kg) and dipyridamole (200 mg/kg) caused the greatest decrease in infarct size compared with higher dose regime of triflusal (30 mg/kg) and dipyridamole (200 mg/kg) (P <.01), triflusal (30 mg/kg) alone (P <.07), and vehicle-treated controls.. The lower dose combination of dipyridamole and triflusal appears to be more effective than triflusal alone after MCAO-induced cerebral ischemia. Therefore, there is a strong rationale to continue to examine the protective effects of triflusal and dipyridamole after cerebral ischemia.

Topics: Animals; Brain; Cytoprotection; Dipyridamole; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Rats, Wistar; Salicylates

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-Zn

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Brain; Brain Ischemia; Cytokines; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley; Salicylates

Topics: Aspirin; Clopidogrel; Coronary Disease; Cost Savings; Desensitization, Immunologic; Drug Hypersensitivity; Drug Substitution; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Salicylates; Ticlopidine

Topics: Aged; Humans; Male; Photosensitivity Disorders; Salicylates; Thromboembolism; Urticaria

Topics: Aged, 80 and over; Facial Dermatoses; Humans; Male; Photosensitivity Disorders; Platelet Aggregation Inhibitors; Salicylates; Skin Tests

The manufacture of porous polycaprolactone (PCL) scaffolds containing three different drugs, namely 5-fluorouracil, nicotinamide and triflusal, was investigated in this work with the aim of obtaining bioactive systems with controlled drug delivery capabilities. The scaffolds were prepared by means of a supercritical CO2 (scCO2) foaming technique by optimizing the drug loading process. This was achieved by dissolving the drugs in organic solvents miscible with scCO2 and by mixing these drug/solvent solutions with PCL powder. The as prepared mixtures were further compressed to eliminate air bubbles and finally processed by the scCO2 foaming technique. ScCO2 saturation and foaming conditions were optimized to create the porosity within the samples and to allow for the concomitant removal of the organic solvents. Physical and chemical properties of porous scaffolds, as well as drug content and delivery profiles, were studied by HPLC. The results of this study demonstrated that the composition of the starting PCL/drug/solvent mixtures affected polymer crystallization, scaffold morphology and pore structure features. Furthermore, it was found that drug loading efficiency depended on both initial solution composition and drug solubility in scCO2. Nevertheless, in the case of highly scCO2-soluble drugs, such as triflusal, loading efficiency was improved by adding a proper amount of free drug inside of the pressure vessel. The drug delivery study indicated that release profiles depended mainly upon scaffolds composition and pore structure features.

Topics: Carbon Dioxide; Drug Delivery Systems; Fluorouracil; HeLa Cells; Humans; Niacinamide; Polyesters; Salicylates; Tissue Scaffolds

Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi-mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent-metabolite pharmacokinetic model, based on a two-compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: Ks , the active-form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active-form platelets; Kel-PRP , the apparent rate constant of platelets; and ε, an intrinsic activity parameter. This semi-mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half-life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi-mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.

Topics: Adult; Blood Platelets; Cilostazol; Clopidogrel; Half-Life; Humans; Models, Theoretical; Platelet Aggregation; Platelet Aggregation Inhibitors; Retrospective Studies; Salicylates; Tetrazoles; Ticlopidine; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Drug Hypersensitivity; Drug Tolerance; Female; Humans; Hypersensitivity, Immediate; Male; Middle Aged; Platelet Aggregation Inhibitors; Salicylates; Skin Diseases

Topics: Aspirin; Carotid Arteries; Clinical Trials as Topic; Endarterectomy, Carotid; Guidelines as Topic; Humans; Ischemic Attack, Transient; Platelet Aggregation Inhibitors; Salicylates; Stents; Stroke

Ischemia/reperfusion (I/R) is a condition that stimulates an intense inflammatory response. No ideal treatment exists. Triflusal is an antiplatelet salicylate derivative with anti-inflammatory effects. S-adenosylmethionine is a metabolic precursor for glutathione, an endogenous antioxidant. Dextromethorphan is a low-affinity N-methyl-D-aspartate receptor inhibitor. There is evidence that these agents modulate some of the pathways involved in I/R physiopathology. Intestinal I/R was induced in rats by clamping the superior mesenteric artery for 60 minutes, followed by 60 minutes of reperfusion. Rats either received saline or the drugs studied. At the end of the procedure, serum concentrations of tumor necrosis factor-alpha (TNF-alpha), malonaldehyde (MDA), and total antioxidant capacity (TAC) were determined and intestinal morphology analyzed. I/R resulted in tissue damage, serum TNF-alpha and MDA elevations, and depletion of TAC. All drugs showed tissue protection. Only triflusal reduced TNF-alpha levels. All drugs lowered MDA levels, but only triflusal and S-adenosylmethionine maintained the serum TAC.

Topics: Animals; Antioxidants; Dextromethorphan; Intestines; Male; Malondialdehyde; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reperfusion Injury; S-Adenosylmethionine; Salicylates; Tumor Necrosis Factor-alpha

Inflammation has been associated with the two classic lesions in the Alzheimer's (AD) brain, amyloid deposits and neurofibrillary tangles. Recent data suggest that Triflusal, a compound with potent anti-inflammatory effects in the central nervous system in vivo, might delay the conversion from amnestic mild cognitive impairment to a fully established clinical picture of dementia. In the present study, we investigated the effect of Triflusal on brain Abeta accumulation, neuroinflammation, axonal curvature and cognition in an AD transgenic mouse model (Tg2576). Triflusal treatment did not alter the total brain Abeta accumulation but significantly reduced dense-cored plaque load and associated glial cell proliferation, proinflammatory cytokine levels and abnormal axonal curvature, and rescued cognitive deficits in Tg2576 mice. Behavioral benefit was found to involve increased expression of c-fos and BDNF, two of the genes regulated by CREB, as part of the signal transduction cascade underlying the molecular basis of long-term potentiation. These results add preclinical evidence of a potentially beneficial effect of Triflusal in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Axons; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Agents; Cognition Disorders; Cytokines; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroglia; Plaque, Amyloid; Proto-Oncogene Proteins c-fos; Salicylates

This study reports on a dual drug-eluting stent (DDES) that has an anti-proliferative and an anti-thrombotic in a biodegradable polymer-coated onto a cobalt-chromium stent. The DDES was prepared by spray coating the bare metal stent with a biodegradable polymer loaded with sirolimus and triflusal, to treat against restenosis and thrombosis, respectively. The 2-layered dual-drug coated stent was characterized in vitro for surface properties before and after expansion, as well as for possible delamination by cross-sectioning the stent in vitro. The in vitro anti-platelet behavior of the triflusal-loaded films was investigated by using dynamic platelet adhesion measurements. Additionally, the in vitro degradation and release study of the films and the stents w/single sirolimus and dual sirolimus-triflusal in different formulations were examined. Finally, in vivo studies (in a porcine carotid artery model) were performed for acute thrombosis, inflammation and restenosis at 30 days. The in vitro results show DDES can sustain release both anti-proliferation drug (sirolimus) and anti-thrombosis drug (triflusal), two drugs were controlled in different rates to effectively reduce thrombosis and proliferation at the same time. In vivo results show a significant reduction in restenosis with dual-drug eluting stent compared with the controls (a bare metal stent, a sirolimus coated and a pure polymer-coated stent). The reduction in restenosis with a dual sirolimus-triflusal eluting stent is associated with an inhibition of inflammation, especially thrombus formation, suggesting that such dual-drug eluting stents have a role to play for the treatment of coronary artery disease.

Topics: Animals; Antibiotics, Antineoplastic; Coated Materials, Biocompatible; Drug Delivery Systems; Drug-Eluting Stents; Humans; Hyperplasia; Materials Testing; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Salicylates; Sirolimus; Surface Properties; Swine; Thrombosis

This article from Coma et al. shows that a salicylic acid derivative Triflusal, a platelet aggregation inhibitor and irreversible inhibitor of COX-1, can correct defects in axonal curvature and cognition in an AD transgenic mouse model (Tg2576) (Coma et al., 2010). Here we discuss the controversy over the role of COX-1 in AD, which has not been considered carefully in part due to the presumed adverse gastrointestinal effects of COX-1 antagonism. However, recent clinical data from this group as well as other groups challenges this assumption that COX-1 antagonism will be associated with side effects. Most importantly this article raises critical questions about the role of COX-1, versus COX-2 versus both in Abeta pathogenesis. The animal model data in this article as well as the recently published trial data suggest that COX-1 may play an important role in early pathogenesis and should not be ignored as a potential target for early intervention.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Central Nervous System Agents; Cognition Disorders; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Humans; Membrane Proteins; Mice; Salicylates

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.

Topics: Alkalies; Aspirin; Boron; Carbon; Diamond; Electrochemistry; Electrodes; Glass; High-Throughput Screening Assays; Hydrogen-Ion Concentration; Hydrolysis; Molecular Structure; Particle Size; Salicylates; Salicylic Acid; Surface Properties; Water

The preparation, characterization, and analysis of physicochemical and biological properties of a new bioactive polymer system, based on a copolymer of an acrylic derivative of triflusal (a molecule with chemical structure related to aspirin with antiaggregating activity for platelets) is described and evaluated as thin bioactive coating for vascular grafts and coronary stents. The acrylic monomer derived from triflusal (THEMA) provides random copolymers when it is polymerized with butyl acrylate (BA), according to their reactivity ratios, r(THEMA) = 1.05 and r(BA) = 0.33. The copolymer THBA70, containing a molar composition f(THEMA) = 0.45 and f(BA) = 0.55 presents the optimal properties of stability, flexibility, and adhesion, with a T(g) = 21 ± 2 °C, to be applied as bioactive and biostable coatings for vascular grafts and coronary stents. Thin films of this copolymer system present an excellent biocompatibility and a good inherent antiaggregant activity for platelets.

Topics: Acrylic Resins; Blood Platelets; Blood Vessel Prosthesis; Cell Adhesion; Cell Line; Cell Survival; Coated Materials, Biocompatible; Endothelial Cells; Humans; Microscopy, Electron, Scanning; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Surface Properties

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antigens, CD; Brain Ischemia; Disease Models, Animal; Endothelin-1; Humans; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Platelet Aggregation Inhibitors; Salicylates; Stroke; tau Proteins; Tumor Necrosis Factor-alpha

Microglial cells, known to play key roles in neuroinflammation, can be immunotoxically eliminated from hippocampal slice cultures by treatment with saporin coupled to the microglial receptor Mac1. Considering microglial cells as a target for anti-inflammatory treatment we studied the effects of microglial depletion on anti-inflammatory treatment of mouse hippocampal slice cultures subjected to ischemia-like neurodegeneration, induced by oxygen-glucose deprivation (OGD). Hippocampal slice cultures, derived from 7-day-old mice and grown for 2 weeks, were divided into 8 groups: (1) control cultures; (2) sham-OGD cultures; (3) OGD cultures; (4) OGD cultures treated with triflusal during OGD; (5) microglia-depleted control cultures; (6) microglia-depleted sham-OGD cultures; (7) microglia-depleted OGD cultures; and (8) microglia-depleted OGD cultures treated with triflusal during OGD. The resulting neurodegeneration was quantified by densitometric measurements of cellular uptake of propidium iodide (PI), with focus on the hippocampal CA1 subfield. Subjection of regular cultures to OGD for 30 min induced a significant increase in PI uptake in the CA1 pyramidal cell layer, compared to control cultures. The presence of 100 microM triflusal during OGD protected against OGD-induced neurodegeneration, and reduced the number of OGD-induced NFkB positive-cells correspondingly. Cultures treated with the Mac1-saporin complex for 7 days displayed an almost total loss of microglial cells. When subjected to OGD after microglial depletion, these cultures displayed a significant increase in OGD-induced PI uptake compared to non-depleted cultures. The presence of triflusal during OGD of these cultures reduced neurodegeneration of the irrespective absence of microglia. In accordance with that, the presence of triflusal during OGD significantly inhibited the increase in the number of reactive microglia and proliferative cells in the CA1 pyramidal and dentate granule cell layers. We conclude that immunotoxic microglia depletion significantly increases the susceptibility of CA1 pyramidal cells to neurodegeneration and that the anti-inflammatory drug triflusal still can exert its neuroprotective role following depletion of microglia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Cell Count; Cell Death; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Glucose; Hippocampus; Ischemia; Mice; Mice, Inbred C57BL; Microglia; Nerve Degeneration; Neurons; Neuroprotective Agents; NF-kappa B; Plant Lectins; Propidium; Salicylates; Tissue Culture Techniques

A mechanism for triflusal-induced photoallergy involving complexation of 2-hydroxy-4-trifluoromethylbenzoic acid with site I of human serum albumin and subsequent formation of a covalent adduct by photoreaction between a metabolite and a neighboring lysine residue is proposed. This is supported by the observed photobinding to poly-L-lysine. Thereby, a photoantigen is generated, which is a likely trigger of the immune response.The goal of the work presented herein is to gain deeper insight into the molecular basis of photoallergy mediated by triflusal through its active metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). For this purpose, the interaction between HTB and human serum albumin (HSA) was investigated by fluorescence and laser flash photolysis to monitor inclusion into the protein binding sites through variation in the excited-state properties. A remarkable lengthening of HTB triplet lifetime in the presence of HSA was observed. The use of oleic acid as a displacement probe clearly suggests the preference for dark binding in site I. The mechanism of photobinding was studied by irradiation of HTB in the presence of amino acids, and, in the case of lysine, a photoadduct was detected that arises from nucleophilic attack by the epsilon-amino group to the trifluoromethyl substituent of HTB. Accordingly, photobinding of the metabolite to poly-L-lysine was also observed. Overall, these results are consistent with a mechanism for triflusal photoallergy involving complexation of HTB to site I of HSA and subsequent formation of a covalent photoadduct with one neighboring lysine residue.

Topics: Binding Sites; Dermatitis, Photoallergic; Humans; Lysine; Photolysis; Protein Binding; Salicylates; Serum Albumin; Spectrometry, Fluorescence

The aim of this article was to study the effect of dual drug-eluting stent (DES) on both restenosis and thrombosis in a porcine coronary artery model. This study reports on the use of two drugs coated on the stent to simultaneously minimize both restenosis and thrombosis. The DES was prepared by spray coating a bare metal stent with a biodegradable polymer loaded with sirolimus and triflusal, to treat against restenosis and thrombosis, respectively. The two-layered dual drug-coated stent was characterized in vitro for surface properties before and after expansion, as well as for possible delamination by cross-sectioning the stent in vitro. In vivo animal studies (in a pig model) were then performed for acute thrombosis, inflammation, and restenosis. The results show a significant reduction in restenosis with a stent coated with both drugs compared with the controls (a bare metal stent, a sirolimus-coated, and a pure polymer-coated stent). The reduction in restenosis with a sirolimus/triflusal-eluting stent is associated with an inhibition of inflammation and thrombus formation, suggesting that such dual DES have a role to play for the treatment of coronary artery diseases.

Topics: Animals; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Chromium Alloys; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug Therapy, Combination; Drug-Eluting Stents; Immunosuppressive Agents; Platelet Aggregation Inhibitors; Prosthesis Design; Salicylates; Sirolimus; Swine; Thrombosis; Treatment Outcome

In the NASPEAF (National Study for Prevention of Embolism in Atrial Fibrillation) trial, combination therapy with an anticoagulant and an antiplatelet was more effective than anticoagulation alone in patients with atrial fibrillation. We report long-term follow-up in these patients, including prospective evaluation of different antiplatelet therapies.. This analysis included 574 atrial fibrillation patients. Standard anticoagulation (international normalized ratio [INR] 2.0-3.0) was used as control therapy to compare with anticoagulation (INR 1.9-2.5) plus either triflusal at 600 mg/day, triflusal at 300 mg/day or aspirin at 100 mg/day. The primary endpoint was ischemic or hemorrhagic stroke, a systemic or coronary ischemic event, or cardiovascular death. The mean follow-up was 4.92 years.. Long-term follow-up confirmed that combination therapy with an anticoagulant plus triflusal at 600 mg/day gave significantly better results than anticoagulation alone (hazard ratio [HR]=0.33; 95% confidence interval [CI], 0.14-0.80; P=.014). There was a significantly higher incidence of ischemic events with triflusal at 300 mg/day (P=.031) and of severe bleeding events with aspirin at 100 mg/day (P=.008). The mean INR was similar in the three combination therapy groups. The incidence of severe nongastric bleeding during combination therapy with triflusal was very low (0.3% of patients/year).. Long-term follow-up confirmed that combination antithrombotic therapy with triflusal at 600 mg/day gave significantly better results than anticoagulant monotherapy. The results obtained with combination therapy with triflusal at 300 mg/day and with aspirin at 100 mg/day should be considered provisional because the treatment groups were small and treatment was not randomly assigned.

Topics: Aged; Aspirin; Atrial Fibrillation; Female; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates; Time Factors

This study describes the development and evaluation of an analytical method for the characterization of triflusal (2-acetoxy-4-(trifluoromethyl) benzoic acid) dispersed in sustained delivery systems prepared using supercritical fluid impregnation technology. Characterization assays comprised the determination of the percentage of triflusal and its degradation product impregnated in polymeric supports and further monitoring of the releases of the two drug components over time in physiological conditions. Preliminary delivery profiles were monitored spectrophotometrically using a continuous-flow system. In this case, no selective wavelength for discriminating between triflusal and metabolite was found so that measurements at 225 nm provided overall profiles corresponding to the two compounds. For a more accurate study, a chromatographic method was developed for monitoring the evolution of the concentration of the two components independently. Triflusal and metabolite were separated in a C(18) column and 25 mM acetic acid/acetate (pH 5.0)+methanol (40/60v/v) mobile phase. Several triflusal-polymer samples were prepared under different experimental conditions and release features were evaluated. Excellent delivery systems were obtained with poly(methyl)methacrylate beads treated at 40 degrees C and 190 bar for 48 h using supercritical carbon dioxide as a solvent. These samples showed a constant sustained release of drug for several weeks.

Topics: Chromatography, Supercritical Fluid; Delayed-Action Preparations; Hydrogen-Ion Concentration; Salicylates; Solubility; Spectrophotometry; Technology, Pharmaceutical

Carotid residual mural thrombus predisposes to recurrent thrombosis and/or distal embolization (i.e. cerebrovascular ischemia).. Our aims were (i) to analyze and compare the efficacy of aspirin, triflusal, and its main metabolite 2-hydroxy-4-trifluorometylbenzoic acid (HTB) on secondary thrombus growth; and (ii) evaluate to what extent the three Cox-1 inhibitors influenced vascular Cox-1/Cox-2 expression and endothelial prostacyclin synthesis.. In a rabbit model of ex vivo thrombosis, a fresh mural thrombus was formed on damaged vessels at flow conditions typical of mild and severe carotid stenoses. The effects of Cox-1 inhibitors administered both intravenously (i.v.) (aspirin 5 mg kg(-1), triflusal 10 mg kg(-1), and HTB 10 mg kg(-1)) and orally (p.o.) (8 days; aspirin 30 mg kg(-1) day(-1), and triflusal 40 mg kg(-1) day(-1)) on secondary thrombus growth were assessed by In-(111)deposited platelets and compared with a placebo control. Arterial Cox-1/Cox-2 expression after 8-day treatment was evaluated at mRNA and protein levels. Additionally, a drug-related dose-dependent in vitro assay was performed for endothelial PGI(2) release measurement (Cox-2 activity).. All Cox inhibitors similarly and significantly (P < 0.05) reduced secondary thrombus formation after i.v. and p.o. administration versus placebo control. Treatments exerted no effect on vascular Cox-1 mRNA whereas Cox-2 mRNA was moderately reduced by aspirin and triflusal (placebo 100% +/- 9%, aspirin 70% +/- 2% and triflusal 70% +/- 2%; P < 0.05). Cox-2 protein levels were slightly higher in the triflusal versus aspirin group (placebo 100% +/- 6%, aspirin 35% +/- 10% and triflusal 61% +/- 9%; P < 0.005 versus placebo). Interestingly, in vitro, HTB solely maintained endothelial PGI(2) synthesis levels similar to the control.. At a similar level of efficacy in inhibiting secondary thrombosis, triflusal seems to better preserve Cox-2 expression than aspirin and its metabolite HTB was able to protect endothelial prostacyclin production.

Topics: Animals; Aspirin; Base Sequence; Blood Vessels; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; DNA Primers; Endothelium, Vascular; Fibrinolytic Agents; In Vitro Techniques; Male; Perfusion; Rabbits; Recurrence; RNA, Messenger; Salicylates; Thrombosis

Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat.. Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured.. Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion.. The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.

Topics: Animals; Aspirin; Brain Ischemia; Disease Models, Animal; Drug Therapy, Combination; Male; Rats; Rats, Wistar; Salicylates

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.

Topics: Algorithms; Alkalies; Aspirin; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Platelet Aggregation Inhibitors; Polyethylene Glycols; Quaternary Ammonium Compounds; Salicylates; Salicylic Acid; Sodium Dodecyl Sulfate; Sodium Hydroxide; Spectrophotometry, Ultraviolet; Static Electricity; Surface-Active Agents; Water

The nuclear factor (NF)-kappaB signaling pathway is an important intracellular mediator of cardiac hypertrophy. The aim of the present study was to determine whether triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), a salicylate derivative used as antiplatelet agent, and its active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) inhibit cardiac hypertrophy in vitro and in vivo by blocking the NF-kappaB signaling pathway. In cultured neonatal rat cardiomyocytes, HTB (300 microM, a concentration reached in clinical use) inhibited phenylephrine (PE)-induced protein synthesis ([3H]leucine uptake), induction of the fetal-type gene atrial natriuretic factor (ANF), and sarcomeric disorganization. Assessment of the effects of triflusal in pressure overload-induced cardiac hypertrophy by aortic banding resulted in a significant reduction in the ratio of heart weight to body weight and in a reduction of the mRNA levels of the cardiac hypertrophy markers ANF and alpha-actinin compared with untreated banded rats. Electrophoretic mobility shift assay revealed an increase in the NF-kappaB binding activity in cardiac nuclear extracts of banded rats that was prevented by triflusal treatment. It is noteworthy that banded rats treated with oral triflusal, compared with untreated rats, showed enhanced protein levels of IkappaBalpha, which forms a cytoplasmic inactive complex with the p65-p50 heterodimeric complex. Finally, HTB increased phospho-IkappaBalpha levels in neonatal cardiomyocytes and inhibited proteosome activity, suggesting that this drug prevented proteosome-mediated degradation of IkappaBalpha. These results indicate that triflusal, a drug with a well characterized pharmacological and safety profile currently used as antiplatelet, inhibits cardiomyocyte growth by interfering with the NF-kappaB signaling pathway through a post-transcriptional mechanism involving reduced-proteosome degradation of IkappaBalpha.

Topics: Animals; Aspirin; Base Sequence; Cardiomegaly; DNA Primers; Electrophoretic Mobility Shift Assay; Immunoprecipitation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; RNA Processing, Post-Transcriptional; Salicylates; Signal Transduction

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Drug Therapy, Combination; Humans; Platelet Aggregation Inhibitors; Salicylates; Thromboembolism; Treatment Outcome; Warfarin

Topics: Aged; Atrial Fibrillation; Death, Sudden, Cardiac; Geriatrics; Humans; Platelet Aggregation Inhibitors; Salicylates

Triflusal is a fluorinated derivative of acetylsalicylic acid (ASA) with demonstrated antithrombotic activity. Recently, evidence for a neuroprotective effect has been obtained. The aim of this study was to compare the neuroprotective effects of the main metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid, HTB) and the ASA metabolite salicylic acid (SA) in an in vitro model of anoxia-reoxygenation in rat brain slices. Rat brain slices (n=10 per group) were subjected to a period of anoxia followed by 180 min reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and LDH efflux, a biochemical marker of cell death. Various concentrations (10, 100 and 1,000 microM) of triflusal, HTB, ASA or SA were tested. Triflusal at 10, 100 and 1,000 microM decreased LDH efflux in rat brain slices after anoxia/reoxygenation by 24%, 35% and 49% respectively. This effect was proportionately greater than that of ASA (0%, 13% and 32%). The results with HTB were similar to those with triflusal, whereas SA showed a greater protective effect than ASA (13%, 33% and 35%). The antioxidant effects of HTB and SA on the biochemical mechanisms of cell damage studied here were also greater than the effects of triflusal and ASA, a finding attributable mainly to the decrease in lipid peroxidation and to the ability of HTB to also increase glutathione levels. The triflusal metabolite reduced inducible NO synthase activity by 18%, 21% and 30%, whereas SA inhibited this activity by 9%, 17% and 23%. Triflusal and HTB led to greater increases in NO synthase than ASA or AS. In conclusion, the metabolite HTB plays an important role in the neuroprotective effect of triflusal, at least in the experimental model of anoxia-reoxygenation tested here.

Topics: Animals; Aspirin; Brain Chemistry; Dinoprostone; Glutathione; Hypoxia, Brain; In Vitro Techniques; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Nerve Tissue Proteins; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reperfusion Injury; Salicylates; Thiobarbituric Acid Reactive Substances

Topics: Cerebrovascular Disorders; Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Humans; Platelet Aggregation Inhibitors; Salicylates; Ticlopidine

Clinical data suggest that Alzheimer disease (AD) and stroke together potentiate cognitive impairment. Our rat model demonstrates that this interaction may be mediated through inflammatory cells and pathways. Thus, anti-inflammatory agents such as Triflusal, a nonsteroidal anti-inflammatory agent (NSAID), may provide neuroprotection for susceptible neurons in AD and cerebral ischemia.. AD was modeled by cerebroventricular injections of beta-amyloid (Abeta25-35) and subcortical lacunar infarcts by striatal endothelin injections. Inflammatory mechanisms were examined by immunohistochemical analysis. Behavioral tasks were assessed with the Montoya staircase test.. Triflusal reduced pathologic and inflammatory markers and functional deficits in rats receiving Abeta or endothelin alone but was less effective in the more severe pathology of the combined Abeta/endothelin model.. Higher doses or more prolonged treatment with NSAIDs may be required for more effective neuroprotection in combined AD and stroke conditions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Astrocytes; Behavior, Animal; Brain; Brain Ischemia; Corpus Striatum; Cytokines; Disease Models, Animal; Endothelins; Glial Fibrillary Acidic Protein; Hippocampus; Immunohistochemistry; Inflammation; Microglia; Neurons; Peptides; Rats; Rats, Wistar; Salicylates; Temperature

The new platelet antiaggregant Triflusal or 2-acetoxy-4-trifluoromethylbenzoic acid presents a structural analogy to acetylsalicylic acid (ASA). Alkaline hydrolysis of triflusal was studied in the presence and absence of cationic micelles of N-cetyl-N-ethyl-N,N-dimethylammonium bromide (CDEABr) at different KOH concentrations and different temperatures (25, 30, and 37 degrees C) using a spectrophotometric method. The influence of potassium bromide concentration upon alkaline hydrolysis at 25 degrees C is also discussed. At constant [KOH] pseudofirst-rate constant (k(obs)) decreased with increasing [CDEABr] at concentrations greater than the CMC and also decreased with increasing [KBr] at constant [KOH] and [CDEABr]. To explain the effect of cationic micelles of CDEABr upon alkaline hydrolysis, the pseudophase ion exchange model was used. The values of the micellar properties such as the critical micelle concentration, the degree of micellar ionization and the neutralized fraction of the head group obtained by conductivity measurements were determined previously.

Topics: Algorithms; Alkalies; Bromides; Chemical Phenomena; Chemistry, Physical; Drug Stability; Electric Conductivity; Hydrolysis; Indicators and Reagents; Kinetics; Micelles; Platelet Aggregation Inhibitors; Potassium Compounds; Salicylates; Surface-Active Agents; Temperature

Topics: Aspirin; Cerebral Infarction; Humans; Pilot Projects; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Salicylates; Stroke; Treatment Outcome

Acetylsalicylic acid (ASA) is the most widely used drug in the prevention of ischemic vascular accidents, mainly because of its antithrombotic effect. Recently, evidence of a neuroprotective effect has appeared. The aim of this study was to evaluate the neuroprotective effect of triflusal, a fluorinated derivative of ASA, in a model of anoxia-reoxygenation in rat brain slices. Rats (n=10 per group) were treated for 7 days with 1, 10 or 50 mg/kg/day p.o. of triflusal or ASA or solvent (control group), then brain slices were obtained and subjected to a period of anoxia followed by 180 min of reoxygenation. We measured oxidative stress parameters (lipid peroxidation, glutathione system), prostaglandins (PGE(2)), nitric oxide pathway activity (NO) (nitrites+nitrates, constitutive and inducible NO synthase activity) and cell death (lactate dehydrogenase (LDH) efflux). Triflusal decreased cell death in rat brain slices subjected to reoxygenation after anoxia by 21%, 42% and 47% with 1, 10 and 50 mg/kg/day, respectively. This effect was proportionately greater than the effect of ASA (0%, 25% and 24%). The antioxidant effects of triflusal on the biochemical mechanisms of cell damage studied here were also greater than the effects of ASA: lipid peroxidation was reduced by 29%, 35% and 36% with triflusal, and 0%, 19% and 29% with ASA. Inducible NO synthase activity was reduced by 25%, 27% and 30% with triflusal, and 0%, 25% and 24% with ASA. Triflusal can be considered an alternative to ASA as a neuroprotective agent, at least in the experimental model of anoxia-reoxygenation used in the present study.

Topics: Analysis of Variance; Animals; Aspirin; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Hypoxia; In Vitro Techniques; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Nitrates; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidative Stress; Oxygen; Platelet Aggregation Inhibitors; Prostaglandins; Rats; Rats, Wistar; Salicylates

Topics: Diabetes Mellitus, Type 2; Diagnosis, Differential; Drug Eruptions; Eczema; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Myocardial Infarction; Patch Tests; Platelet Aggregation Inhibitors; Salicylates

The in vitro aqueous behaviour of a metacryloyloxyethyl [2-(acetyloxy)-4-(trifluoromethyl)]benzoate (THEMA)/N,N'-dimethylacrylamide (DMA) copolymer with a THEMA molar content of 39% (labeled THDMA39) has been investigated. This composition has been selected to achieve a system able to keep both the non-water solubility during the release and the resorbability (and the water solubility) after the completion of the drug release. This copolymer exhibited, at pH 7.4, a constant release during several months, very interesting for a long term treatments required for the application of some cardiovascular devices. A kinetic model has been developed to explain the pseudo-zero-order kinetics of the release process. This model, which considers (from the aqueous studies) a linear increase with time of the amount of water present in the polymeric matrix, has been able to fit adequately the experimental data.

Topics: Acrylamides; Biocompatible Materials; Blood Platelets; Drug Design; Free Radicals; Humans; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Magnetic Resonance Spectroscopy; Models, Chemical; Platelet Aggregation; Platelet Aggregation Inhibitors; Polymers; Salicylates; Thrombin; Time Factors; Toluene; Water

Topics: Acenocoumarol; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; International Normalized Ratio; Male; Middle Aged; Mitral Valve Stenosis; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Salicylates; Warfarin

Topics: Aspirin; Clinical Trials as Topic; Drug Therapy, Combination; Fibrinolytic Agents; Forecasting; Humans; Platelet Aggregation Inhibitors; Salicylates; Stroke

A rapid, selective and sensitive high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), in rat and human plasma. HPLC analysis was carried out using a 5-microm particle size, C18-bonded silica column and acetonitrile-methanol-water (25:10:65, v/v/v) as the mobile phase and UV detection at 234 nm. Furosemide was used as the internal standard. The method involved extraction with an acetonitrile-chloroform mixture (60:40, v/v) and evaporation to dryness with nitrogen stream. The chromatograms showed good resolution and sensitivity and no interferences by plasma constituents. The mean absolute recovery for human plasma was 93.5 +/- 4.2% for triflusal and 98.5 +/- 3.1% for HTB. The lower limits of quantification of triflusal and HTB in human plasma were 20 and 100 ng/ml, respectively. The calibration curves in human plasma were linear over the concentration range 0.02-5.0 microg/ml for triflusal and 0.1-200.0 microg/ml for HTB with correlation coefficients greater than 0.999 and with inter- or intra-day coefficients of variation (CV) not exceeding 10.0%. This assay procedure was applied to the study of metabolite pharmacokinetics of triflusal and HTB in rat and human.

Topics: Animals; Area Under Curve; Chromatography, High Pressure Liquid; Humans; Male; Rats; Reproducibility of Results; Salicylates; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Topics: Arthritis, Rheumatoid; Echocardiography, Transesophageal; Female; Humans; Middle Aged; Mitral Valve; Mitral Valve Prolapse; Platelet Aggregation Inhibitors; Recurrence; Salicylates; Stroke; Treatment Outcome

The fluorinated salicylate triflusal has been shown to have a neuroprotective effect after an excitotoxic lesion to the postnatal brain. In this regard, the aim of this study was to elucidate whether neuroprotection was associated with changes in the expression of proinflammatory molecules such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), or cyclooxygenase-2 (COX-2), well-known mediators of oxidative stress and inflammation, mechanisms underlying secondary damage occurring after excitotoxic/ischemic brain injury.. Postnatal day 9 rats received an intracortical injection of N-methyl-D-aspartate followed by oral administration of triflusal (30 mg/kg) 8 hours later. Ten or 24 hours after lesion, animals were killed, and brain sections processed for the immunohistochemical demonstration of IL-1beta, TNF-alpha, iNOS, and COX-2.. Besides a reduction in the neurodegenerative area, triflusal strongly decreased iNOS immunolabeling at both survival times analyzed, attenuating iNOS immunoreactivity in astroglial cells and infiltrated neutrophils. Additionally, a moderate reduction in COX-2, IL-1beta, and TNF-alpha was observed. Triflusal decreased neuronal and microglial COX-2 expression at 10 and 24 hours after lesion and microglial and astroglial expression of IL-1beta and TNF-alpha at 24 hours after lesion. TNF-alpha expression in neuronal cells at 10 hours after lesion was, however, maintained.. This study suggests that triflusal neuroprotection is associated with a decrease of iNOS and other inflammatory mediators and therefore may constitute a good therapeutic agent in pathological situations in which regulation of inflammatory genes constitutes a relevant step in the outcome of the neurodegenerative event.

Topics: Administration, Oral; Animals; Astrocytes; Cyclooxygenase 2; Disease Models, Animal; Inflammation Mediators; Interleukin-1; Isoenzymes; Microglia; Microinjections; N-Methylaspartate; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Neutrophil Infiltration; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Long-Evans; Salicylates; Somatosensory Cortex; Tumor Necrosis Factor-alpha

Triflusal is an irreversible inhibitor of platelet cyclooxygenase. Triflusal significantly reduced the incidence of nonfatal myocardial infarction in patients with unstable angina. Antithrombotic properties have also been demonstrated in patients with aortocoronary vein grafting, coronary angioplasty, peripheral arteriopathy and cerebrovascular disease. Moreover, in diabetic patients it has a protective effect against retinal microangiopathy, improves renal flow and reduces proteinuria. The drug has a high tolerability and has low incidence of side effects, with prevalence of gastrointestinal and skin disorders. Because of its demonstrated effectiveness and its good handling, we decided to use Triflusal in treatment of geriatric patients with peripheral arteriopathy. Often these patients have a diffused arteriopathic disease which can be associated with chronic diseases. For this reason there are severe problems of compliance due to contemporary administration of several drugs; so the utilization of effective drugs, without side effects, promotes a safer clinical management of patients.. Between April 2000 and March 2001, we treated with Triflusal 70 patients, over 65 years old, with peripheral arteriopathy. The group comprises patients who had undergone traditional vascular surgery, or endovascular surgery and patients treated exclusively with drug therapy. During the follow-up we obser-ved the possible clinical development of side effects of the drug reported in the literature (nausea, vomiting, etc.).. One patient, already affected by gastroduodenal disease, suspended the therapy because of severe epigastric burning.. The follow-up of the patients goes on in order to evaluate the tolerability and handling of Triflusal, observing a larger number of patients.

Topics: Age Factors; Aged; Aged, 80 and over; Arterial Occlusive Diseases; Female; Follow-Up Studies; Humans; Male; Patient Compliance; Platelet Aggregation Inhibitors; Risk Factors; Salicylates; Time Factors

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-kappaB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-alpha (TNF-alpha) activated NF-kappaB as judged from both the appearance of kappaB-binding activity in the nuclear extracts, the degradation of IkappaB proteins in the cell lysates, and the activation of IkappaB kinases using an immunocomplex kinase assay with glutathione S-transferase (GST)-IkappaB proteins as substrates. 3. HTB up to 3 mM did not inhibit the nuclear translocation of NK-kappaB/Rel proteins as judged from electrophoretic mobility-shift assays; however, HTB inhibited the degradation of IkappaBbeta without significantly affecting the degradation of both IkappaBalpha and IkappaBepsilon. 4. In keeping with their inhibitory effect on IkappaBbeta degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST-IkappaBbeta elicited by TNF-alpha, without affecting the phosphorylation of GST-IkappaBalpha. 5. The effect of both HTB and triflusal on kappaB-dependent trans-activation was studied by assaying the expression of both cyclo-oxygenase-2 (COX-2) and vascular cell adhesion molecule-1 (VCAM-1). HTB and triflusal inhibited in a dose-dependent manner the expression of COX-2 and VCAM-1 mRNA and the induction of COX-2 protein at therapeutically relevant concentrations. 6. These findings show the complexity of the biochemical mechanisms underlying the activation of NF-kappaB in the different cell types and extend the anti-inflammatory effects of HTB and triflusal to neural cells.

Topics: Astrocytoma; Blotting, Western; Brain Neoplasms; Cyclooxygenase 2; DNA, Complementary; Electrophoresis; Humans; Indicators and Reagents; Isoenzymes; Membrane Proteins; Neoplasm Proteins; Neurons; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; Salicylates; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1

Triflusal is a platelet antiaggregant drug with photoallergic side effects. However, it is considered a prodrug since it is metabolized to 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)--the pharmacologically active form. HTB was found to be photolabile under various conditions. Its major photodegradation pathway appears to be the nucleophilic attack at the trifluoromethyl moiety. The involvement of the triplet state in the photodegradation has been unequivocally proved by direct detection of this transient in laser flash photolysis and by quenching experiments with oxygen, cyclohexadiene and naphthalene. Finally, the photobinding of HTB to proteins such as bovine serum albumin has been demonstrated using ultraviolet-visible (UV-Vis) and fluorescence spectroscopy. Nucleophilic groups present in the protein appear to be responsible for the formation of covalent drug photoadducts, which is the first step involved in the photoallergy shown by triflusal.

Topics: Dermatitis, Photoallergic; Photochemistry; Platelet Aggregation Inhibitors; Protein Binding; Salicylates; Serum Albumin, Bovine; Spectrometry, Fluorescence

Nuclear factor-kappaB (NF-kappaB) and the signal transducer and activator of transcription 3 (STAT3) are important transcription factors regulating inflammatory mechanisms and the glial response to neural injury, determining lesion outcome. In this study we evaluate the ability of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid), an antiplatelet agent inhibitor of NF-kappaB activation, to improve lesion outcome after excitotoxic damage to the immature brain.. Postnatal day 9 rats received an intracortical injection of the excitotoxin N-methyl-D-aspartate (NMDA) and oral administration of triflusal (30 mg/kg) either as 3 doses before NMDA injection (pretreatment) or as a single dose 8 hours after NMDA injection (posttreatment). After survival times of 10 and 24 hours, brains were processed for toluidine blue staining, tomato lectin histochemistry, and glial fibrillary acidic protein, NF-kappaB, and STAT3 immunocytochemistry.. NMDA-lesioned animals that were not treated with triflusal showed activation of NF-kappaB in neuronal cells at first and in glial cells subsequently. Animals that received pretreatment with triflusal showed a strong downregulation of neuronal and glial NF-kappaB but a similar development of the glial response and an equivalent lesion volume compared with nontreated animals. In contrast, animals receiving triflusal posttreatment showed increased early neuronal NF-kappaB but a reduction in the subsequent glial NF-kappaB, accompanied by important downregulation of the microglial and astroglial response and a drastic reduction in the lesion size. STAT3 activation was not affected by triflusal treatment.. Triflusal posttreatment diminishes glial NF-kappaB, downregulates the glial response, and improves the lesion outcome, suggesting a neuroprotective role of this compound against excitotoxic injury in the immature brain.

Topics: Administration, Oral; Animals; Astrocytes; Brain; DNA-Binding Proteins; Down-Regulation; Drug Administration Schedule; Glial Fibrillary Acidic Protein; Microglia; Microinjections; N-Methylaspartate; Neuroglia; Neuroprotective Agents; NF-kappa B; Platelet Aggregation Inhibitors; Rats; Rats, Long-Evans; Salicylates; STAT3 Transcription Factor; Trans-Activators

Topics: Aspirin; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Salicylates

The thrombotic process is a multicellular phenomenon in which not only platelets are involved but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal reduced platelet aggregation by stimulating nitric oxide (NO) production by neutrophils. The aim of the present study was to evaluate whether the in vivo treatment with triflusal could also modify the ability of neutrophils to produce NO. Furthermore, the role of NO released by neutrophils on platelet aggregation and secretion was also tested.. The study was performed in 12 healthy volunteers of 32 +/- 6 years of age. The volunteers were treated with triflusal (600 mg/day) for 5 days and platelets and neutrophils were isolated before and after treatment. The ability of neutrophils to produce NO and the capacity of inhibiting platelet aggregation and secretion of transforming growth factor-beta (TGF-beta) were assessed.. After the treatment with triflusal we obtained the following results: a) an increase in NO production by neutrophils; b) potentiation of the inhibition of platelet aggregation by neutrophils, an effect that was reverted by incubating neutrophils with an L-arginine antagonist, L-NAME, and c) the presence of neutrophils reduced the release of TGF-beta by platelets measured as index of platelet secretion by a NO-independent mechanism.. Triflusal (600 mg/day/5 days) stimulated NO production by neutrophils. After the treatment with triflusal, neutrophils inhibited both platelet aggregation and secretion. The antiaggregating effect of neutrophils was an NO-dependent mechanism while the inhibition of platelet secretion mediated by neutrophils after the treatment with triflusal was an NO-independent mechanism.

Topics: Adult; Blood Platelets; Citrulline; Cyclic GMP; Guanosine Monophosphate; Humans; Neutrophils; Nitric Oxide; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Transforming Growth Factor beta

To evaluate the impact of the application of objectives relating to the rational use of medication and to assess the possible effect of these objectives on pharmaceutical expenditure.. A non-randomised intervention study with control.. Santiago de Compostela Primary Care (PC) Area.. After the inclusion and exclusion criteria were applied, both the intervention group (IG) and the control group (CG) consisted of 31 doctors. Those in the IG belonged to the reformed PC model, whereas those in the CG did not.. Four blocks of objectives on the rational use of medication were included in the Pact signed by reformed-model doctors and the management. The study lasted three years (1996-1998) for the objective of lowering the prescription of low-therapeutic-utility (LTU) drugs, and two years (1997-1998) for lowering the prescription of antihypertensives, Triflusal and quinolones.. The difference between both groups was 1.7 fewer packs of LTU drugs per 1000 users and per day in the IG (95% CI, 0.9-2.6) and 1768 pesetas less (95% CI, 801-2733). These differences were still greater among pensioners. The difference between the two groups in terms of total pharmaceutical cost was 7379 pesetas less in the IG (95% CI, 708-14,049) than in the CG. The differences between the groups for the remaining objectives (antihypertensives, Triflusal and quinolones) in no case reached statistical significance.. The pharmaceutical objectives of the pact were partly achieved: a drop in LTU drug prescription was seen, with an indirect reduction in overall expenditure, but no differences were found in the prescription of antihypertensives, triflusal or quinolones.

Topics: Antihypertensive Agents; Costs and Cost Analysis; Drug Prescriptions; Drug Utilization; Humans; Platelet Aggregation Inhibitors; Primary Health Care; Quinolones; Retirement; Salicylates; Spain; Urban Population

In this study we have evaluated the in vivo ability of triflusal (2-acetoxy-4-tri-fluoromethylbenzoic acid) to inhibit constitutive nuclear factor-kappa B (NF-kappaB) activation in the brain of postnatal rats. One week old Long-Evans black hooded rat pups received three oral administrations of triflusal (30 mg/kg) and were sacrificed at 9 days of age. After fixation, brains were cut in a cryostat and processed immunocytochemically for the demonstration of NF-kappaB. In control postnatal rats, NF-kappaB is constitutively present in some neuronal populations and in glial cells of white matter tracts. In contrast, triflusal treated rats showed a drastic downregulation of neuronal and glial NF-kappaB, both in the number of labelled cells and in the intensity of staining. The inhibition of NF-kappaB activation could be an important step in the modulation of inflammatory processes occurring after several pathological conditions.

Topics: Administration, Oral; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Brain Chemistry; Immunohistochemistry; Neuroglia; Neurons; NF-kappa B; Rats; Rats, Long-Evans; Salicylates

Triflusal is a fluorinated aspirin derivative with antiplatelet properties, which is used in Spain for the management and prevention of thromboembolic disease.. A 91-year-old female developed a systemic photosensitivity reaction 15 days after beginning triflusal preventive treatment (300 mg/12 h) for prior transient ischaemic attack. Photobiological study showed an abnormal response to light in areas exposed to ultraviolet B and A radiation, with a photopatch test positive to both triflusal and its main metabolite. These observations suggested a causal relation between triflusal and the clinical findings, as described in previous reports.. The few cases reported to date and the clinicopathological features of this case suggested an immunological response as the most likely cause of the reaction.

Topics: Aged; Aged, 80 and over; Female; Humans; Ischemic Attack, Transient; Photosensitivity Disorders; Platelet Aggregation Inhibitors; Salicylates

To evaluate the adequacy to thromboembolic disease prophylaxis protocol in patients with heart disease.. Cross-sectional study.. Patients older than 14 years affected of heart disease in a semi-urban health primary-care clinic with a population of 10,610 persons and 5582 clinical records.. Data about age, sex, cardiovascular risk factors, heart disease, prophylactic treatment and its adequacy to the protocol of the "thromboembolic disease commission" of the reference hospital were analysed.. Age 67 +/- 13 years (mean +/- SD). Cardiovascular risk factors: hypertension 40%, diabetes 33%, dyslipemia 15%, smoking 21%. Heart disease: ischemic cardiopathy 48%, atrial fibrillation 15%, valvulopathy 19%, dilated myocardiopathy 4% and other 14%. In 20% of cases had two different affections (80% with atrial fibrillation). Prophylactic therapy: 52% of patients were under prophylactic treatment (35% antiaggregation, 18% anticoagulation). Among antiaggregants, drugs used were acetylsalicylic acid 73.5%, triflusal 14.7%, dipyridamole, 8.8% and ticlopidine 3%. In 53% of people without prophylactic treatment antiaggregation criteria were present. 15% of patient under antiaggregation therapy did not meet antiaggregation criteria, and 6% fulfilled anticoagulation criteria. 67% treatments accorded the reference protocol, without significant differences between kind of heart disease or sex. The only statistically significant difference was found in age: 46% of patients older than 80 year were correctly treated, in front 75% adequacy in younger people.. Prophylactic antithrombotic therapy was according the reference protocol in 67% of cases. In older patients, with greater risk of thromboembolic disease, the adequacy is worse.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Cross-Sectional Studies; Dipyridamole; Female; Heart Diseases; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Factors; Salicylates; Sex Factors; Thromboembolism; Ticlopidine

The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Inflammation; Isoenzymes; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Membrane Proteins; NF-kappa B; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Salicylates

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the activation of NF-kappaB elicited by tumour necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVEC) was tested. 2. The expression of the mRNA of vascular cell adhesion molecule-1 (VCAM-1) was studied as an example of a gene the expression of which is regulated by NF-kappaB. To extend these findings to other systems, the induction of nitric oxide synthase in rat adherent peritoneal macrophages was studied. 3. Both HTB and triflusal were more potent than aspirin or salicylate as inhibitors of the nuclear translocation of NF-kappaB. The calculation of the IC50 values showed approximately 2 mM for HTB, 4 mM for aspirin and >4 mM for salicylate. 4. Comparison of the potency of these compounds on VCAM-1 mRNA expression showed complete inhibition by both triflusal and HTB at a concentration of 4 mM whereas aspirin and salicylate produced only 36-43% inhibition at the same concentration. 5. Inhibition of NF-kappaB activation was also observed in rat peritoneal macrophages stimulated via their receptors for the Fc portion of the antibody molecule with IgG/ovalbumin immune complexes. This was accompanied by a dose-dependent inhibition of nitrite production by the L-arginine pathway via iNOS. IC50 values for this effect were 1.13+/-0.12 mM (triflusal), 1.84+/-0.34 (HTB), 6.08+/-1.53 mM (aspirin) and 9.16+/-1.9 mM (salicylate). 6. These data indicate that the incorporation of a 4-trifluoromethyl group to the salicylate molecule strongly enhances its inhibitory effect on NF-kappaB activation, VCAM-1 mRNA expression and iNOS induction, irrespective of the presence of the acetyl moiety involved in the inhibition of cyclo-oxygenase.

Topics: Animals; Aspirin; Cell Line; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Macrophages, Peritoneal; NF-kappa B; Nitric Oxide; Platelet Aggregation Inhibitors; Rats; RNA, Messenger; Salicylates; Thrombin; Tumor Necrosis Factor-alpha; Umbilical Veins; Vascular Cell Adhesion Molecule-1

Topics: Aged; Cerebrovascular Disorders; Drug Eruptions; Humans; Male; Platelet Aggregation Inhibitors; Salicylates; Skin Tests

Recent studies have suggested that the protective anti-ischemic effects of acetylsalicylic acid are stronger than the inhibition of platelet thromboxane A2 synthesis. Since ischemic events still occur in acetylsalicylic acid-treated patients, the development of new drugs with more powerful protective effects is needed. We compared the effects of a new platelet antiaggregating drug, 2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and of acetylsalicylic acid on the interaction between human neutrophils and platelets, examining the capability of neutrophils to generate nitric oxide (NO). Triflusal, in the presence of neutrophils, showed a greater antiplatelet potency than acetylsalicylic acid to inhibit thrombin-induced platelet activation. Significant stimulation of NO-mediated mechanisms in the presence of acetylsalicylic acid or triflusal was demonstrated by the following findings: (1) increased metabolism of arginine to citrulline, (2) increase of cGMP in the platelet/neutrophil system and (3) the inhibitory action of the L-arginine (L-Arg) competitive analogue, NG-nitro-L-arginine-methyl ester (L-NAME), which was reversed by L-Arg. Triflusal increased the stimulation of NO synthesis by neutrophils more than did of acetylsalicylic acid. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), alone or in combination with acetylsalicylic acid, did not modify NO production by neutrophils. Therefore, the whole molecule of triflusal is needed to stimulate NO production by neutrophils. Our results show that, in the presence of neutrophils, triflusal exerts an antiplatelet effect greater than that of acetylsalicylic acid, demonstrating a more powerful stimulation of the NO/cGMP system. The present results indicate that it is possible to develop new and more potent acetylsalicylic acid-related antiplatelet drugs for the prevention of the myocardial ischemic/reperfusion processes.

Topics: Aspirin; Cyclic GMP; Cyclooxygenase Inhibitors; Humans; Neutrophils; Nitric Oxide; Platelet Aggregation Inhibitors; Salicylates

The place of platelet antiaggregants in the aetiology of intracerebral hemorrhage (IH) has not been extensively studied.. To analyze the characteristics of IH in patients treated with platelet antiaggregants and the possible clinical and prognostic differences from other primary IH.. A retrospective study of patients admitted to hospital with primary IH from 1985 to 1997. The cases were IH patients while being treated with platelet antiaggregants. For each case we selected two controls with IH and similar age and IH risk factors. The following data was analyzed: start of clinical condition; type, dose, indication and duration of treatment with antiaggregants; mortality, localization, volume and extension of IH to the ventricles. The last four variables were compared with the control group using the ji squared test (chi 2) and the t student test.. 21one patients had a primary IH while being treated with antiaggregants: 20 with salicylates (17 aspirin and 3 riflusal) and one with ticlopidine. The dose of aspirin was 500 mg or less in 90% of the cases. In the group treated with salicylates, this was given for more than 20 months in 90% of the cases. Initially there was no clinical progression in any case. No significant differences were observed between the variable compared, although there was a tendency to greater volume, extension to the ventricles and mortality in the group treated with antiaggregants.. More studies with larger numbers of patients are necessary to be able to confirm the tendencies observed.

Topics: Aged; Aged, 80 and over; Aspirin; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prognosis; Retrospective Studies; Risk Factors; Salicylates

To find out how many patients older than 64 years of age seen in a primary health care (PHC) centre receive antiplatelet drugs for secondary prevention of coronary heart disease (CHD), as well as by whom they are prescribed, which drug is chosen, and what are its contraindications, unwanted effects and motives for ending therapy.. Description of all cases of CHD among patients older than 64, identified through the audit of clinical records.. Urban health care centre with 23,702 inhabitants, with 2,742 over 64, 2,660 of whom have clinical records.. Patients over 64 with CHD, seen in the health centre within 1993.. Age, sex, type of CHD, therapy with a platelet aggregation inhibitor, drug used, dose, prescriptor, adverse events, contraindications.. We identified 179 cases of CHD, a prevalence of 6.7%, of which 60.9% were male. 94 patients received an antiplatelet drug: aspirin (88.3%), dypiridamol and triflusal (5.3% each) and ticlopidine (1 case). 111 patients were adequately treated, including 84 given aspirin or ticlopidine, 12 patients in which therapy was ended due to adverse events, and 15 patients in which use of antiaggregant drugs was contraindicated. All prescriptions originating from general practitioners were for aspirin, while specialists prescribed other drugs in 11% of cases.. Two-thirds of patients with CHD were correctly treated. Aspirin is the antiaggregant drug most frequently used, particularly among PHC physicians. Even low doses of aspirin were associated with interruptions of therapy due to adverse events.

Topics: Age Factors; Aged; Aged, 80 and over; Aspirin; Dipyridamole; Drug Prescriptions; Family Practice; Female; Humans; Male; Medical Audit; Medicine; Myocardial Ischemia; Platelet Aggregation Inhibitors; Prevalence; Primary Health Care; Salicylates; Spain; Specialization; Ticlopidine; Urban Population

Topics: Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Platelet Aggregation Inhibitors; Salicylates

The ex vivo effect of triflusal and acetylsalicylic acid (ASA) on platelet interaction with the subendothelium using the Baumgartner perfusion system (wall shear rate 350 s-1) was assessed in blood from 10 healthy volunteers who given a 15-day course of triflusal 600 mg per day and ASA 400 mg per day in a cross-over trial. The percentage of platelets on the subendothelium showed a decrease of 62% in samples from subjects on ASA and a decrease of 93% in those from subjects on triflusal (P < 0.005). The percentage of the subendothelial surface covered by platelets was reduced by 23.3% after treatment with ASA, mainly due to inhibition of aggregates (75.2%), and by 29.9% after treatment with triflusal, mainly due to inhibition of aggregates (89.6%) and of adhesion (25%). The subendothelial surface covered by activated platelets (adhesions and thrombi) showed 32.5% inhibition after treatment with triflusal and 11.6% after treatment with ASA (P < 0.043 vs. triflusal). In the in vitro experiments, 10 mumol.l-1 triflusal did not modify the percentage of the subendothelium covered by platelets. HTB 1 mmol.l-1 inhibited adhesion (26%) and aggregates (18%). We conclude that HTB participates in the ex vivo effects of triflusal on the platelet-subendothelium interaction.

Topics: Adult; Animals; Aspirin; Blood Platelets; Endothelium, Vascular; Humans; Male; Perfusion; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits; Salicylates

MCA occlusion in animals is a common model for experimental stroke. In previous studies we have shown that one of the factors, which influence evolution of an infarct is microthrombosis in the area of infarction and in the surrounding brain tissue. The present study was undertaken for assessment of the number of microthrombi and of the size of brain infarcting in rats treated with the antiaggregatory substance Triflusal. 7 groups of Sprague-Dawley rats, each group consisting of 6 animals, underwent transsphenoidal MCA occlusion. The animals received Triflusal in various amounts from day 2 till day 6. At day 7 animals were decapitated and the brains were fixed in formaldehyde. The brain was dissected at the level of the optic chiasm and embedded in paraffin. Fresh microthrombi were detected py PTAH (Phosphotungstic acid hematoxylin) staining. In each animal the hemisphere with the ischemic lesion as well as the contralateral hemisphere were examined. The area of both hemispheres was calculated by subtraction of the ventricle area from the total brain area of a section. Infarct was defined as the region of necrosis which was sharply demarcated from normal brain. The infarcted area was planimetrically measured to obtain a ratio of infarcted to normal brain. A correlation between the effect of Triflusal, number of microthrombi and size of the infarcted area could be demonstrated. The pathogenetic role of the microthrombi in the evolution of cerebral infarction as well as the effect of Triflusal in different dosages on the number of microthrombi could be clearly assessed by quantitative morphometry.

Topics: Animals; Brain; Brain Damage, Chronic; Capillaries; Cerebral Infarction; Dose-Response Relationship, Drug; Intracranial Embolism and Thrombosis; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Salicylates

2-Hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of triflusal, an antiplatelet drug. The in-vitro binding of HTB to human serum was studied in the presence of different drugs. The results indicate that no statistically significant changes are observed in the HTB binding in the presence of caffeine, theophylline, glisentide, enalapril, cimetidine or warfarin. The free fraction of HTB increases significantly in the presence of the non-steroidal anti-inflammatory drugs studied: diclofenac, ibuprofen, indomethacin, naproxen, piroxicam and salicylic acid. At high concentrations, HTB displaces these anti-inflammatory drugs and also glisentide and warfarin from their protein binding sites.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Binding, Competitive; Drug Interactions; Humans; Platelet Aggregation Inhibitors; Protein Binding; Salicylates; Serum Albumin

2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet antiaggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied. Rats were given a single oral dose of 50 mg.kg-1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC. HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K = intrinsic affinity constant, n = number of binding sites) were K1 = 1.4 x 10(5) l.mol-1, n1 = 1.23, and K2 = 4.1 x 10(3) l.mol-1 and n2 = 3.77. The mean plasma concentration in rats after oral administration was 185 (37) micrograms.ml-1 (protein-free HTB:2.44 (0.77)%). The binding constants in human plasma were K1 = 4.7 x 10(5) l.mol-1, n1 = 1.93, K2 = 4.3 l.mol-1 and n2 = 4.28. The plasma HTB concentration in man (n = 8) was 35 micrograms.ml-1 (Cmax) after a single oral dose of triflusal 300 mg, 172.96 micrograms.ml-1 (Cmax.ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 micrograms.ml-1 (Cmax.ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Blood Proteins; Female; Humans; Orosomucoid; Platelet Aggregation Inhibitors; Protein Binding; Rats; Rats, Inbred Strains; Salicylates; Serum Albumin

1. Triflusal is a salicylic derivative that inhibits platelet aggregation in human whole blood with a minimal inhibition of prostacyclin production. 2. Aspirin inhibits platelet aggregation at concentrations that reduce vascular prostacyclin production.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Humans; In Vitro Techniques; Mesenteric Arteries; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Salicylates; Thromboxane B2

Ischemic cerebral infarcts induce hypercoagulation and microthrombosis, thus leading to vessel occlusion and reduction of local cerebral blood flow. Antiaggregant therapy can reduce the formation of microthrombi. We tested the effect of acetylsalicylic acid (ASA) and triflusal (2-acetoxy-4-tri-fluoromethylbenzonic acid) on the formation of microthrombi after middle cerebral artery (MCA) occlusion. Six groups of rats, each consisting of six animals received either ASA or triflusal at dosages of 12.5, 25 or 50 mg/1,000 g b.wt./day. One control group was sham-operated, in another control group MCA occlusion was performed; both groups received no therapy. The number of microthrombi was counted 7 days after MCA occlusion on paraffin sections. The highest number of microthrombi was found in the group with MCAO and without therapy (mean 28 microthrombi/animal). In treated groups a reduction of the number of microthrombi could be stated. The strongest reduction was achieved in the group treated with 12.5 mg triflusal (mean 5.2). No statistic significant difference in the number of microthrombi was found between the groups treated with 12.5 mg triflusal and 50 mg ASA (mean 8.7) compared to sham-operated control animals (mean 4.3, p greater than 0.05). Treatment with 12.5 mg triflusal was superior to 50 mg ASA in preventing microthrombi formation (p less than 0.05). These results indicate, that in experimental brain ischemia the number of microthrombi can be effectively reduced by application of antiaggregatory drugs.

Topics: Animals; Aspirin; Brain Ischemia; Cerebral Arteries; Intracranial Embolism and Thrombosis; Male; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Salicylates

Triflusal (2-acetoxy-4-trifluormethylbenzoic acid) is a platelet-antiaggregant drug that selectively inhibits thromboxane synthesis with little effect on prostacyclin production. In this study, we evaluated the effect of 5-day administration of 900 mg/day triflusal on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary albumin excretion (UAE), thromboxane B2 (TXB2), 6-ketoprostaglandin F1 alpha (PGF1 alpha), and PGE2 in nine normotensive insulin-dependent diabetic patients with UAE between 30 and 103 micrograms/min. Plasma TXB2 and plasma renin activity (PRA) were also determined. After administration of triflusal, we observed a reduction in microalbuminuria (59 +/- 25 vs. 33 +/- 22 micrograms/min, P less than 0.01), an increase in RPF (648 +/- 119 vs. 722 +/- 134 ml.min-1 x 1.73 m-2, P less than 0.01), and a reduction in filtration fraction (0.24 +/- 0.04 vs. 0.20 +/- 0.03, P less than 0.01). Triflusal produced a significant reduction in both plasma TXB2 (130 +/- 39 vs. 52 +/- 32 pg/ml, P less than 0.02) and urine TXB2 (523 +/- 249 vs. 312 +/- 11 pg/min, P less than 0.02), without changes in PRA and UAE of 6-keto-PGF1 alpha and PGE2. Metabolic control and arterial blood pressure did not change during the study. These results suggest that platelet-antiaggregant therapy can reduce microalbuminuria in diabetic patients. This effect could be mediated by a reduction in the transglomerular hydraulic pressure through a vasodilation of efferent arterioles secondary to renal thromboxane synthesis inhibition.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprostone; Female; Glomerular Filtration Rate; Humans; Male; Platelet Aggregation Inhibitors; Renal Circulation; Renin; Salicylates; Thromboxane B2

Triflusal pharmacokinetics were evaluated in 8 healthy subjects after a single 300 mg dose and after repeated doses of 300 mg every 8 h and 600 mg every 24 h during 13 days, with the aim of establishing a relationship between plasma levels and dosage patterns. Plasma concentrations of triflusal and its main metabolite, 2-hydroxi-4-trifluoromethylbenzoic acid (HTB), were determined by HPLC. Triflusal (t1/2 = 29-35 min) metabolized rapidly into HTB. Four h after the first or last repeated dose administration, triflusal levels could not be detected. After the administration of 300 mg every 8 h, the parameters obtained for HTB were: Cmax-ss = 178 +/- 42 micrograms/ml, tmax-ss = 1.9 +/- 0.7 h, Cmin-ss = 155.6 +/- 41.2 micrograms/ml, Cavg-ss = 168.0 +/- 41.8 micrograms/ml and a t1/2 of 48 +/- 15 h. The parameters obtained for the dosage of 600 mg every 24 h were: Cmax-ss = 153 +/- 40 micrograms/ml, tmax-ss = 2.7 +/- 0.9 h, and a t1/2 of 50 +/- 16 h. No significant differences were observed between the elimination half-life obtained after the single dose and after the two repeated dose regimens studied. This finding suggests that HTB displays a linear pharmacokinetic behaviour.

Topics: Adult; Chromatography, High Pressure Liquid; Half-Life; Humans; Male; Platelet Aggregation Inhibitors; Random Allocation; Salicylates

We have induced the formation of arterial (carotid) and venous (femoral) thrombi in dogs by means of an intima lesion produced by continuous current. The platelets were labeled with 111In oxine. Groups of 7 mongrel dogs received treatment for 7 days prior to the trial: group I, control; group II, 5 mg/kg body weight/day acetylsalicylic acid; group III, 20 mg/kg body weight/day acetylsalicylic acid; group IV, 15 mg/kg body weight/day triflusal + 5 mg/kg body weight/day dipyridamole; group V, 15 mg/kg body weight/day triflusal; and group VI, 5 mg/kg body weight/day acetylsalicylic acid + 5 mg/kg body weight/day dipyridamole. The only effective treatment for arterial thrombosis prevention was that employed in group II (p less than 0.05). Venous thrombosis was prevented in groups II (p less than 0.01), III (p less than 0.01) and VI (p less than 0.01).

Topics: Animals; Aspirin; Dipyridamole; Dogs; Drug Evaluation; Drug Therapy, Combination; Platelet Aggregation Inhibitors; Salicylates; Thrombosis

We have induced the formation of arterial thrombosis in dogs by means of an intima lesion produced by continuous current. The platelets were labeled with 111-In-oxine. Groups of 7 mongrel dogs received treatment for 7 days prior to the trial: Group I, control; Group II, 5 mg/kg body weight/day acetylsalicylic acid; Group III, 20 mg/kg body wt/day acetylsalicylic acid; Group IV, 15 mg/kg body wt/day triflusal + 5 mg/kg body wt/day dipyridamole; Group V, 15 mg/kg body wt/day triflusal; and Group VI, 5 mg/kg body wt/day acetylsalicylic acid + 5 mg/kg body wt/day dipyridamole. The only effective treatment for arterial thrombosis prevention was that employed in Group II (p less than 0.05).

Topics: Animals; Aspirin; Dipyridamole; Dogs; Indium Radioisotopes; Platelet Aggregation Inhibitors; Salicylates; Scintillation Counting; Thrombosis

A study was made on the inhibitory effect of triflusal (600 mg/d X 15) and acetylsalicylic acid (ASA, 400 mg/d X 15) on platelet aggregation in whole blood (WB) and platelet-rich plasma (PRP) induced by ADP (2.5 mumol/l), adrenaline (50 mumol/l), collagen (1 microgram/ml) and arachidonic acid (0.8 mmol/l), in 30 insulin-dependent diabetic patients without vascular complications. Determination was also made of the serum levels of thromboxane B2 (TxB2) and of the plasma levels of 6-keto-PGF1-alpha and of beta-thromboglobulin (B-TG). Both drugs exhibited higher inhibitory effects in WB than in PRP. In WB, a significant difference between triflusal and ASA was observed against ADP-induced aggregation (67% and 46% inhibition respectively, p less than 0.01). Both drugs strongly inhibit the formation of TxB2 in serum (85% and 99%, respectively). Triflusal does not significantly change the plasma levels of 6-keto-PGF1-alpha; ASA, by contrast, causes reduction of over 95% in those plasma levels. The plasma levels of B-TG were not modified by either of the drugs.

Topics: Adult; Aspirin; beta-Thromboglobulin; Diabetes Mellitus, Type 1; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Salicylates; Thromboxane B2

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 malondialdehyde formation induced by arachidonic acid. The IC50 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.

Topics: Alprostadil; Animals; Aorta, Thoracic; Aspirin; Blood Platelets; Drug Interactions; In Vitro Techniques; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Vasodilator Agents

Topics: Adolescent; Adult; Diabetic Retinopathy; Drug Evaluation; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Salicylates

An in vitro and ex vivo study has been made to determine the inhibition of platelet aggregation in human whole blood (WB) and platelet rich plasma by triflusal and its main metabolite HTB (2-hydroxy-4-trifluoromethylbenzoic acid). Triflusal was administered orally at 300 mg x 2/day, for 15 days, to 13 healthy volunteers (ex vivo tests). Triflusal and HTB, at concentrations lower than 1 mM, produced a significant inhibition of platelet aggregation induced by ADP (2.5 microM, final) and collagen (1 microgram/ml, final) in PRP, while about 50% inhibition was induced in WB samples at 0.12 mM. Ex vivo studies also revealed a stronger inhibitory effect of triflusal in WB samples against several inducers; differences were particularly pronounced against ADP (10.6 times more potent in WB). These results suggest an important role of red blood cells and/or leukocytes in the mechanism of action of triflusal. The antiplatelet effect of triflusal in WB was modified when incubated with HTB at therapeutic concentrations. The IC50 value against collagen increased from 82 to 140 microM with 37.5 microM HTB, but decreased in a dose-dependent manner when incubated with higher concentrations of HTB, suggesting that inhibition of platelet cyclooxygenase by HTB masks its negative interaction with triflusal.

Topics: Adenosine Diphosphate; Adult; Collagen; Epinephrine; Humans; In Vitro Techniques; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Thromboxane B2

A study has been made on the in vitro effect of triflusal, acetylsalicylic acid (ASA and their major metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), and salicylic acid (SA), on platelet aggregation in human whole blood. SA exhibited no significant antiplatelet effects (IC50 greater than 2mM) against several inducers; the IC50 values for the other compounds were: triflusal, 140 microM against ADP and 63.2 microM against collagen; HTB, 100 microM against ADP and 260 microM against collagen; ASA 687 microM against ADP and 9.3 microM against collagen. Red blood cells potentiate the antiaggregant effect of HTB and of triflusal, and to a lesser extent, that of ASA; leukocytes primarily potentiate the effect of ASA and, to a lesser extent, that of triflusal.

Topics: Adult; Aspirin; Erythrocytes; Humans; In Vitro Techniques; Leukocytes; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Salicylates; Salicylic Acid

Within 60 sec after intracarotid injection of 0.33 mg/kg arachidonic acid, a pronounced attenuation of electrocortical activity, approaching electrocerebral silence, was induced in the ipsilateral hemisphere of anesthetized and heparinized rats. This effect was a consequence of the cerebrovascular occlusion due to platelet aggregates induced by arachidonic acid. This model has been used to evaluate the protective effect of acetylsalicylic acid (ASA) and of triflusal 2 hr after a single oral dose of 50 mg/kg or after 50 mg/kg, for 5 days. Pentylenetetrazol at 10 mg/kg, i.v. exerts a stimulant effect on CNS, and was used as a positive control. ASA and triflusal exhibit a protective effect in about 35% of animals when acutely administered. After chronic treatments (5 days), the effect of triflusal (60% protection) was superior to that of ASA (27% protection) (p less than 0.01).

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Cerebrovascular Disorders; Electroencephalography; Male; Platelet Aggregation; Rats; Rats, Inbred Strains; Salicylates

Topics: Female; Humans; Middle Aged; Photosensitivity Disorders; Salicylates

The effect of triflusal, acetylsalicylic acid (ASA), and of their principal metabolites 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and salicylic acid (SA), alone or combined with dypiridamole (DIP) and/or PGE1 on cyclic AMP levels in washed rat platelets (37 degrees C, 4 min), has been determined. DIP at 0.1 mM increased cyclic AMP levels by 25%. The effect of triflusal and HTB was significant at therapeutic concentrations of triflusal (1 mM: 36% increase) and HTB (0.5 mM: 37% increase). The effect of HTB was always greater than that of triflusal. ASA, at 1 mM and 5 mM, alone or combined with PGE1 was without effect. When 1 mM triflusal was combined with 0.1 mM DIP an increased effect was obtained (95%). ASA, at the highest concentration tested (5 mM), did not modify the DIP-induced increase of cyclic AMP levels.

Topics: Alprostadil; Animals; Aspirin; Blood Platelets; Cyclic AMP; Dipyridamole; Drug Interactions; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid

The biological effects of a new antiplatelet agent, triflusal, were evaluated in patients with cardiac valvular prostheses. Each patient received 900 mg/day of oral triflusal for 30 days. Triflusal significantly inhibited platelet aggregation induced by adenosine diphosphate (1 to 5 mumol) or epinephrine (12.5 mumol), showing a slight effect on bleeding time (basal: 6 +/- 1.7 min; 30 days of treatment: 8.0 +/- 2.7 min). Serum levels of thromboxane B2 were significantly reduced during treatment, but changes in serum levels of 6-keto-prostaglandin F1 alpha were not observed, suggesting that triflusal does not affect prostacyclin biosynthesis by the vascular wall. The results show that triflusal has a marked inhibitory and selective effect on platelet function in patients with cardiac valvular prostheses.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Female; Heart Valve Prosthesis; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Count; Salicylates

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Female; Fibrinolytic Agents; Male; Rats; Rats, Inbred Strains; Salicylates; Thrombosis

Topics: Animals; Blood Platelets; Cyclooxygenase Inhibitors; Female; Humans; In Vitro Techniques; Male; Rats; Rats, Inbred Strains; Salicylates

Topics: Humans; Platelet Aggregation; Salicylates; Thromboembolism; Vascular Diseases

Topics: Adenosine Diphosphate; Animals; Female; Fibrinolytic Agents; Injections, Intravenous; Lung Diseases; Male; Rats; Rats, Inbred Strains; Salicylates; Thrombosis

Topics: Animals; Male; Rats; Rats, Inbred Strains; Salicylates; Tissue Distribution

Topics: Administration, Oral; Animals; Dogs; Injections, Intravenous; Kinetics; Salicylates

Topics: Animals; Aspirin; Chemical Phenomena; Chemistry; Organophosphates; Platelet Aggregation; Rats; Salicylates

A group of 15 patients, suffering of chronic ischaemia of the lower limbs, were treated with triflusal, a new antiaggregant and antithrombotic agent, at the dose of 300 mg/day, during the first 90 days after artery by-pass grafting. Clinical exploration of patients included: physical inspection, pulses palpation, intermittent claudication (in metres), arteriography before surgery, and postoperative evolution of oscillometric and Doppler indexes. Determinations of platelet aggregation, induced by ADP, epinephrine and collagen, as well as of prothrombin time, platelet adhesiveness, and of thromboelastography parameters in PRP ane PPP were also carried out. Biochemical and hematological data were determined; gastric tolerance and other side effects were written down. Results show a clear improvement of all patients due to surgery, but with triflusal, it has been possible to maintain a prophylactic effect without thrombosis of the graft or of the distal vessel of patients, during the postoperative period. Actually, lower limbs temperature and pulses were maintained, with a good capillary content and with an improved walking distance. No changes in prothrombin time an platelet adhesiveness, have been observed. Five patients showed a clear hypoaggregant tendency, and thromboelastography in PRP indicates a statistically significant increase of R and K parameters as well as a decrease of am. It must be noticed the absence of gastric, hepatic, renal or metabolic side effects and no haemorrhagic lesions were observed. In conclusion, the treatment of these patients with triflusal prevents the otherwise frequent appearance of postoperative thrombosis in this kind of arterial surgery.

Topics: Adult; Aged; Blood Vessel Prosthesis; Drug Evaluation; Endarterectomy; Female; Fibrinolytic Agents; Humans; Ischemia; Leg; Male; Middle Aged; Postoperative Complications; Salicylates; Thrombosis

Triflusal is a new antithrombotic agent, structurally similar to acetylsalicylic acid (ASA), which has been shown to possess a different pharmacological profile, suggesting a different mechanism of action for both compounds. To confirm this hypothesis we have studied, comparatively, the inhibition by triflusal and ASA of the activity of several enzymes involved in the equilibrium of platelet haemostasis, namely, prostaglandin-synthetase system (PG-synthetase), cyclo-oxygenase, thromboxane-synthetase and cAMP-phosphodiesterase. Results indicate that trilfusal is 60% less potent as inhibitor of cyclooxygenase (biological method) and of prostaglandin biosynthesis (spectrophotometric method ) than ASA. On the contrary, triflusal is five times more potent than ASA as inhibitor of cAMP phosphodoesterase. Inhibition of thromboxane-synthetase by both compounds is negligible and without physiological significance. These results suggest a mechanism of action of trifusal that might explain the different pharmacological profile between triflusal and ASA as antithrombotic agents.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Aspirin; Cattle; Cyclooxygenase Inhibitors; Fibrinolytic Agents; Horses; In Vitro Techniques; Microsomes; Myocardial Contraction; Oxidoreductases; Salicylates; Sheep; Thrombosis; Thromboxane-A Synthase

Topics: Animals; Arachidonic Acids; Cricetinae; Disease Models, Animal; Fibrinolytic Agents; Injections, Intravenous; Lung Diseases; Mice; Rabbits; Respiration Disorders; Salicylates; Thrombosis