Disgren® [Triflusal]

Pharmacological properties

triflusal (inn - triflusalum) reduces thromboxane biosynthesis by irreversible inhibition of platelet cog; in a therapeutic dose does not affect the biosynthesis of prostacyclin, since vascular tsog is affected to a small extent. the main metabolite of triflusal - 2-hydroxy-4- (trifluoromethyl) benzoic acid (gtb) is also an inhibitor of (platelet) platelet tsog and due to its long-term t½ (34 h) promotes the antithrombotic effect of triflusal. both triflusal and gtb can increase the concentration of cAMP in platelets by inhibiting platelet PDE. in addition, in vitro and ex vivo, it was demonstrated that triflusal stimulates the release of nitric oxide in human neutrophils, which also contributes to the antithrombotic effect. in in vivo experiments in healthy volunteers after the use of triflusal at a dose of 600 mg after 24 hours, arachidonic acid-induced platelet aggregation decreased by 65%. repeated use of triflusal (600 mg / day for 7 days) led to inhibition of aggregation of 50–75% of platelets induced by arachidonic acid, adf, epinephrine or collagen.

Pharmacokinetics After oral administration, triflusal is rapidly absorbed, the absolute bioavailability is 83-100%. Under the influence of esterases, the drug quickly hydrolyzes, turning into the main active metabolite - GTB. In the urine, a secondary conjugated GTB metabolite, glycine, is determined. T_½ is 0.53 ± 0.12 hours for triflusal and 34.3 ± 5.3 hours for GTB. Excretion occurs mainly by the kidneys (renal clearance is 60% in 48 hours). In urine, non-metabolized triflusal, GTB and the metabolite of GTB, glycine, are determined.

After the use of triflusal by healthy volunteers at a dose of 300 and 900 mg C_max triflusal in plasma is 3.2 ± 1.9 and 11.6 ± 1.7 μg / ml, respectively, C_max for GTB is 36.4 ± 6.1 and 92.7 ± 17.1 μg / ml, respectively. Time required to reach C_max (t_max), is 0.88 ± 0.26 h for triflusal and 4.96 ± 1.37 h for GTB at a dose of 900 mg. The pharmacokinetic parameters of GTB with long-term use of triflusal (300 mg 3 times a day or 600 mg 1 time per day for 13 days) indicate that C_max GTB in plasma is stable and amounts to 178 ± 42 and 153 ± 37 μg / ml, respectively. GTB in therapeutic concentration binds to albumin in blood plasma by 98–99%; this compound is not significantly affected by caffeine, theophylline, glisentide (not registered in Ukraine), enalapril, cimetidine and warfarin. However, the concentration of the free fraction of GTB increases significantly with the simultaneous use of NSAIDs (diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, salicylic acid). In a high concentration, GTB replaces NSAIDs, sulfonylureas and warfarin derivatives in the protein binding sites, as they exhibit affinity for the same protein binding sites (can be interchanged depending on the degree of their affinity with the protein and the concentration of the substituted substance).

In elderly volunteers, after applying 300 mg of triflusal 2 times a day, the equilibrium concentration of triflusal and GTB in blood plasma is reached within 3-5 days. AUC, C indicators_max and t_max in elderly volunteers do not significantly differ from the indicators recorded in young volunteers; T_½ in blood plasma is 0.92 ± 0.16 h for triflusal and 64.4 ± 6.6 h for GTB (higher than that of young volunteers). However, these features of pharmacokinetics in the elderly do not have clinical significance and there is no need to adjust the dose.

In patients with end-stage chronic renal failure, receiving chronic hemodialysis, indicators of the concentration of GTB in blood plasma before and after hemodialysis were identical.

Indications

• Prevention of repeated vascular disorders of an ischemic nature: myocardial infarction; stable and unstable angina; cerebrovascular non-hemorrhagic circulatory disorders of a transient or permanent nature; prevention of occlusion after undergoing a coronary artery bypass surgery.

Application

Apply inside. the recommended dose is 600 mg (2 capsules) per day once or in two divided doses, or 900 mg (3 capsules) per day in three divided doses. the drug is recommended to be used during meals.

Contraindications

Increased individual sensitivity to the active substance and / or other derivatives of salicylic acid. peptic ulcer of the stomach and / or duodenum, including in the inactive phase. acute bleeding.

Side effects

Most often, they develop on the part of the gastrointestinal tract and usually pass after a few days even without drug withdrawal.

From the skin: rash, itching.

From the side of the central nervous system: headache, feeling of anxiety, fainting, convulsions.

From the side of the organ of hearing: tinnitus, hypacusia.

On the part of the sensory organs: violation of taste sensations.

From the gastrointestinal tract: dyspeptic disorders.

From the cardiovascular system: hypertension, vascular (extracardial) disorders.

From the respiratory system: choking, inflammatory reactions from the upper respiratory tract.

On the part of the blood system: anemia, impaired coagulation (nosebleeds, hematoma, purpura, bleeding gums).

From the genitourinary system: hematuria, urinary tract infection.

General reactions: fever, catarrhal effects from the respiratory tract.

Particular cases of photosensitization are described.

special instructions

Clinical experience in the use of the drug in patients with renal or hepatic insufficiency is limited, therefore it is necessary to use triflusal with extreme caution.

In patients with severe renal failure undergoing hemodialysis, the plasma concentration of the main metabolite of triflusal - GTB does not significantly change, so there is no need to adjust the dose.

The drug should be used with caution in patients with an increased risk of bleeding. When treating with triflusal, it is necessary to use with caution drugs that increase the risk of bleeding (acetylsalicylic acid and other NSAIDs). With planned surgical interventions, it is necessary to weigh the risk of bleeding and, if necessary, discontinue Disgren treatment at least 7 days before the planned surgical intervention.

During pregnancy and breastfeeding. During animal studies, there was no direct or indirect negative effect on the course of pregnancy, fetal development, childbirth and the postpartum period. There are no data on the use of triflusal during pregnancy, so it is not recommended to use the drug during this period. There is no data on the penetration of triflusal into breast milk, therefore, the expected benefits for the mother and the likely risk to the fetus / baby must be weighed. For the period of treatment, the mother should refrain from breastfeeding.

Children. The safety and effectiveness of the drug in children have not been established, so it is not recommended to use the drug in pediatric practice.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Not described, but it is necessary to consider the possibility of adverse reactions from the central nervous system.

Interactions

In vitro experiments showed an increase in the concentration of the free fraction of the main metabolite of triflusal - gtb in the presence of NSAIDs. on the other hand, with an increase in the concentration of GTB, the effects of NSAIDs, glisentide (not registered in Ukraine) and warfarin increase. if necessary, a dose adjustment of these drugs is possible if they are used simultaneously with triflusal.

In patients with acute myocardial infarction, the safety of triflusal was evaluated simultaneously with thrombolytic agents (a recombinant tissue plasminogen activator and streptokinase), while the number of cases of intracranial hemorrhage was less than in patients taking acetylsalicylic acid (0.1% compared with 1.1 %, p = 0.04).

Overdose

Not described. when taking the drug in a high dose, symptoms of intoxication with salicylates may develop (headache, tinnitus, dizziness, nausea, vomiting, tachypnea). in this case, it is necessary to stop using the drug and prescribe symptomatic therapy.

Storage conditions

At temperatures up to 25 ° c.