Effects of Triflusal and Clopidogrel on the Secondary Prevention of Stroke Based on Cytochrome P450 2C19 Genotyping / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: To compare the efficacy and safety of antiplatelet agents for the secondary prevention of ischemic stroke based on cytochrome P450 2C19 (CYP2C19) polymorphisms. METHODS: This study was a prospective, multicenter, randomized, parallel-group, open-label, blind genotype trial. First time non-cardiogenic ischemic stroke patients were enrolled and screened within 30 days. Participants were randomized to receive either triflusal or clopidogrel for secondary stroke prevention. The primary outcome was the time from randomization to first recurrent ischemic stroke or hemorrhagic stroke. RESULTS: The required sample size was 1,080 but only 784 (73%) participants were recruited. In patients with a poor CYP2C19 genotype for clopidogrel metabolism (n=484), the risk of recurrent stroke among those who received triflusal treatment was 2.9% per year, which was not significantly different from those who received clopidogrel treatment (2.2% per year; hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.60–2.53). In the clopidogrel treatment group (n=393), 38% had good genotypes and 62% poor genotypes for clopidogrel metabolism. The risk of recurrent stroke in patients with a good CYP2C19 genotype was 1.6% per year, which was not significantly different from those with a poor genotype (2.2% per year; HR, 0.69; 95% CI, 0.26–1.79). CONCLUSIONS: Whilst there were no significant differences between the treatment groups in the rates of stroke recurrence, major vascular events, or coronary revascularization, the efficacy of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype status remains unclear.

Pharmacokinetic Study on Single Dose and Multiple Dose of Triflusal Capsule in Healthy Volunteers / 中国药房

OBJECTIVE:To study the pharmacokinetic characteristics of triflusal capsule in healthy volunteers. METHODS:In ran-domized test,36 healthy volunteers were randomly divided into 3 groups. They were given low-dose,medium-dose and high-dose of Triflusal capsule(300 mg,600 mg and 900 mg),qd,for one day,and then pharmacokinetic study of single dose of Triflusal capsule was conducted;Triflusal capsule medium-dose group was continuously given medicine for 13 days,and then pharmacokinetic study of multiple dose of Triflusal capsule was conducted. The plasma concentration of triflusal was determined by LC-MS/MS,and Zorbax SB-C18 column was used with methanol-0.2% formic acid (80:20,V/V) at the flow rate of 0.2 ml/min. ESI was adopted in MRM mode,negative ion detection was carried out,quantitative analysis m/z 247.1→161.1(triflusal),m/z 294.0→250.0(internal standard, diclofenac sodium). Pharmacokinetic parameters were calculated by using WinNonlin 6.2 software,and the difference of them were compared. RESULTS:The linear range of triflusal were 0.05-20 μg/ml. The main pharmacokinetic parameters of triflusal capsules high-dose,medium-dose and low-dose groups were as follows:t1/2 were (0.45 ± 0.20),(0.47 ± 0.10),(0.43 ± 0.20) h;tmax were (0.56±0.20),(0.60±0.20),(0.47±0.40)h;cmax were(3.30±0.98),(10.65±3.26),(13.96±4.88)μg/ml;AUC0-8 h were(3.99±0.93), (13.29±1.72),(19.62±6.78)μg·h/ml;within dose of 300-900 mg,linear relationship was found between cmax,AUC0-8 h and dose(R2=0.954,0.986). When reaching stable state of multiple dose,average blood concentration was(0.71±0.20)μg/ml;main pharmacokinetic parameters were as follows:AUCs(17.10±4.82)μg·h/ml,t1/2(0.49±0.10)h,tmax(0.85±0.62)h,cmax(11.58±3.99)μg/ml,AUC0-8 h (16.99±4.84)μg·h/ml,AUC0-∞(17.08±4.81)μg·h/ml;accumulation factor(1.28±0.40). tmax and t1/2 of single dose were similar to those of multiple dose. CONCLUSIONS:LC-MS/MS can determine the content of triflusal in human plasma rapidly and accurately, and accumulation phenomena exist in healthy Chinese volunteers,which shows linear pharmacokinetic characteristics.

Effect of Triflusal on Primary Vascular Dysregulation Compared with Aspirin: A Double-Blind, Randomized, Crossover Trial

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: Triflusal was more effective and demonstrated a more consistent impact on the improvement of symptoms and blood flow in patients with PVD than aspirin.

Comparative study of triflusal and ticlopidine on anti-platelet aggregatory effect and side effects

BACKGROUND AND PURPOSE: Platelet aggregation plays an important role in thrombogenesis. Thus antiplatelet agents, such as aspirin and ticlopidine, have been in usage to prevent for recurrent ischemic stroke. Triflusal is known to selectively inhibit cyclooxygenase in platelet rather than in vessel wall. And thus can be more beneficial in its antiplatelet aggregatory effect. There has been no comparative study between triflusal and ticlopidine on its antiplatelet aggregatory effect and side effects till now. Our comparative study between these two agents is to provide useful information on clinical utilization. METHODS: Triflusal(900mg/day) and ticlopidine(500mg/day) were administered in 31 and 37 patients, who suffered from acute ischemic stroke. Their efficacy in platelet aggregation and the incidence of clinical and laboratory side effects were compared in one week and one month after the administration of the drugs. RESULTS: Platelet aggregation was more effectively inhibited in triflusal group, especially induced by collagen or epinephrine(p<0.01). No significant difference was noted in the incidence of side effects in both groups. In five patients of the ticlopidine group, the drug was withdrawn due to skin rash and/or increased liver enzymes. CONCLUSION: Triflusal had more effectively inhibited platelet aggregation in this study. Severe side effects even requiring discontinuation of the drug were noted in five patients of ticlopidine group.

The Inhibitory Effect of Triflusal (Disgren)on the Platelet Aggregation in Healthy Volunteers: Impedance Method with the Whole Blood

BACKGROUND: Antiplatelet drugs play an important role in the prevention and treatment of coronary artery diseases. Triflusal, an antiplatelet drug structually related to acetylsalicylic acid, selectively inhibits the cyclooxygenase of platelet and thromboxane A2 formation. However there is a controversy about the clinical dosage and the quantitative evaluation of the platelet antiaggregatory effect of triflusal. In this study we have evaluated the platelet antiaggregatory effect and cost-effective dosage of triflusal in the whole blood of healthy volunteers. METHODS: Using the whole blood of 50 healthy people, we performed a baseline platelet aggregation function test induced by adenosine diphosphate (ADP) and collagen. The subjects were subdivided into 3 treated groups (300 mg, 600 mg, 900 mg). We compared the platelet aggregation effect between the baseline results and 2 weeks after triflusal administration. RESULTS: Triflusal inhibited the platelet aggregation induced by ADP and collagen in the 600 mg administration group most effectively. The platelet aggregation induced by collagen was inhibited dose-dependently. The definite inhibitory responders (% inhibition > or = 25) for platelet aggregation induced by collagen were more common than those induced by ADP (33% vs 27% in 300 mg, 71% vs 53% in 600 mg, 78% vs 39% in 900 mg). There were no serious clinical side-effects except gastrointestinal trouble. One volunteer in the 900 mg treated group discontinued the treatment due to epigastric pain. CONCLUSION: We conclude that triflusal has a dose-dependent inhibitory effect on platelet aggregation induced by collagen and that the most effective dosage for platelet antiaggregation effect is 600 mg per day.

The Inhibitory Effect of Triflusal (Disgren)on the Platelet Aggregation in Healthy Volunteers: Impedance Method with the Whole Blood

BACKGROUND: Antiplatelet drugs play an important role in the prevention and treatment of coronary artery diseases. Triflusal, an antiplatelet drug structually related to acetylsalicylic acid, selectively inhibits the cyclooxygenase of platelet and thromboxane A2 formation. However there is a controversy about the clinical dosage and the quantitative evaluation of the platelet antiaggregatory effect of triflusal. In this study we have evaluated the platelet antiaggregatory effect and cost-effective dosage of triflusal in the whole blood of healthy volunteers. METHODS: Using the whole blood of 50 healthy people, we performed a baseline platelet aggregation function test induced by adenosine diphosphate (ADP) and collagen. The subjects were subdivided into 3 treated groups (300 mg, 600 mg, 900 mg). We compared the platelet aggregation effect between the baseline results and 2 weeks after triflusal administration. RESULTS: Triflusal inhibited the platelet aggregation induced by ADP and collagen in the 600 mg administration group most effectively. The platelet aggregation induced by collagen was inhibited dose-dependently. The definite inhibitory responders (% inhibition > or = 25) for platelet aggregation induced by collagen were more common than those induced by ADP (33% vs 27% in 300 mg, 71% vs 53% in 600 mg, 78% vs 39% in 900 mg). There were no serious clinical side-effects except gastrointestinal trouble. One volunteer in the 900 mg treated group discontinued the treatment due to epigastric pain. CONCLUSION: We conclude that triflusal has a dose-dependent inhibitory effect on platelet aggregation induced by collagen and that the most effective dosage for platelet antiaggregation effect is 600 mg per day.