38 research outputs found
BETA-ADRENORECEPTORS GENETIC POLYMORPHISM CONNECTION WITH BETA-BLOKER THERAPY EFFICACY IN PATIENTS WITH CARDIOVASCULAR DISORDERS
At present it is obvious that genetic peculiarities of patients are the major reason for individual differences in pharmacological responses to (Ξ²-adrenoblockers. Furthermore ADRB1 gene polymorphism is responsible for the efficiency of (Ξ²-adrenoblockers. Thus, a real prospect exists for an individualized approach to administration of (Ξ²-adrenoblockers and selection of dosage based on patientβs genotype, which must undoubtedly increase efficiency of the administered therapy. Reviewfocuses on gene polymorphism responsible for (Ξ²-adrenoblockers pharmacodynamics and on the clinical significance of the polymorphism detection to individualize drug therapy based on patientβs genotype
ΠΠ»ΠΈΠ½ΠΈΠΊΠΎ-ΡΠ°ΡΠΌΠ°ΠΊΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΡΠ΅Ρ Π½ΠΎΠ»ΠΎΠ³ΠΈΠΈ ΠΏΠ΅ΡΡΠΎΠ½Π°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΡΠ΅ΡΠ΄Π΅ΡΠ½ΠΎ-ΡΠΎΡΡΠ΄ΠΈΡΡΡΡ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ: ΡΠΎΠΊΡΡ Π½Π° ΠΏΡΡΠΌΡΠ΅ ΠΎΡΠ°Π»ΡΠ½ΡΠ΅ Π°Π½ΡΠΈΠΊΠΎΠ°Π³ΡΠ»ΡΠ½ΡΡ
One of the main causes for adverse reactions development is not taking into account the pharmacokinetics of drugs and the dose. Pharmacokinetics of drugs is mostly defined by the cytochrome P-450 isoenzymes activity, carboxylesterases and many other isoenzymes of drug metabolism, as well as ADME transporters (P-gp etc.) which take part in the process of drug metabolism. The activity of these isoenzymes is defined by the genetic aspects of patients and non-genetic aspects such as comorbidity and drug-drug interactions. The development of complex algorithms for personalization of therapy based on the results of pharmacogenetic studies and in the form of a decision support system will play an important role in reduction of adverse drug reactions. A lot can be achieved for personalization of Direct Oral Anticoagulants for treatment of cardiovascular diseases. New approaches are being developed based on the results of pharmacogenetic and pharmacokinetic testing that will help diminish adverse effects of drugs.ΠΠ΄Π½ΠΎΠΉ ΠΈΠ· Π²Π°ΠΆΠ½ΡΡ
ΠΏΡΠΈΡΠΈΠ½ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΡΡΠΎΠ³Π΅Π½Π½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΠΎΡΠ°ΠΆΠ΅Π½ΠΈΠΉ Π²Π½ΡΡΡΠ΅Π½Π½ΠΈΡ
ΠΎΡΠ³Π°Π½ΠΎΠ² ΡΠ²Π»ΡΠ΅ΡΡΡ Π½Π΅Π΄ΠΎΡΡΠ΅Ρ Π²ΡΠ°ΡΠ°ΠΌΠΈ ΠΏΡΠΈ Π²ΡΠ±ΠΎΡΠ΅ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΡΠ΅Π΄ΡΡΠ² (ΠΠ‘) ΠΈ ΠΈΡ
ΡΠ΅ΠΆΠΈΠΌΠΎΠ² Π΄ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈΠ½Π΄ΠΈΠ²ΠΈΠ΄ΡΠ°Π»ΡΠ½ΡΡ
ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠ΅ΠΉ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΊΠΈΠ½Π΅ΡΠΈΠΊΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π² ΠΎΡΠ³Π°Π½ΠΈΠ·ΠΌΠ΅ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠ°, ΠΊΠΎΡΠΎΡΠ°Ρ Π²ΠΎ ΠΌΠ½ΠΎΠ³ΠΎΠΌ ΠΎΠΏΡΠ΅Π΄Π΅Π»ΡΠ΅ΡΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ ΡΠ΅ΡΠΌΠ΅Π½ΡΠ°ΡΠΈΠ²Π½ΡΡ
ΡΠΈΡΡΠ΅ΠΌ Π±ΠΈΠΎΡΡΠ°Π½ΡΡΠΎΡΠΌΠ°ΡΠΈΠΈ ΠΠ‘ (ΡΠ΅ΡΠΌΠ΅Π½ΡΡ I ΡΠ°Π·Ρ β ΠΈΠ·ΠΎΡΠ΅ΡΠΌΠ΅Π½ΡΡ ΡΠΈΡΠΎΡ
ΡΠΎΠΌΠ° Π -450, ΠΊΠ°ΡΠ±ΠΎΠΊΡΠΈΡΡΡΠ΅ΡΠ°Π·Ρ ΠΈ Π΄Ρ., ΡΠ΅ΡΠΌΠ΅Π½ΡΡ II ΡΠ°Π·Ρ β N-Π°ΡΠ΅ΡΠΈΠ»ΡΡΠ°Π½ΡΡΠ΅ΡΠ°Π·Π° ΠΈ Π΄Ρ.) ΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡΡ ΡΡΠ°Π½ΡΠΏΠΎΡΡΠ΅ΡΠΎΠ², ΡΡΠ°ΡΡΠ²ΡΡΡΠΈΡ
Π² ΠΏΡΠΎΡΠ΅ΡΡΠ°Ρ
Π²ΡΠ°ΡΡΠ²Π°Π½ΠΈΡ, ΡΠ°ΡΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ ΠΈ Π²ΡΠ²Π΅Π΄Π΅Π½ΠΈΡ ΠΠ‘ (Π -Π³Π»ΠΈΠΊΠΎΠΏΡΠΎΡΠ΅ΠΈΠ½, ΡΡΠ°Π½ΡΠΏΠΎΡΡΠ΅ΡΡ ΠΎΡΠ³Π°Π½ΠΈΡΠ΅ΡΠΊΠΈΡ
Π°Π½ΠΈΠΎΠ½ΠΎΠ² ΠΈ ΠΊΠ°ΡΠΈΠΎΠ½ΠΎΠ²). ΠΡΠΈ ΡΡΠΎΠΌ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΡΠΈΡ
ΡΠΈΡΡΠ΅ΠΌ Π·Π°Π²ΠΈΡΠΈΡ ΠΎΡ Π³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠ΅ΠΉ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² (ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠΈΠ·ΠΌΡ ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²ΡΡΡΠΈΡ
Π³Π΅Π½ΠΎΠ² β ΠΏΡΠ΅Π΄ΠΌΠ΅Ρ ΠΈΠ·ΡΡΠ΅Π½ΠΈΡ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠ³Π΅Π½Π΅ΡΠΈΠΊΠΈ) ΠΈ Π½Π΅Π³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠ°ΠΊΡΠΎΡΠΎΠ², ΡΠ°ΠΊΠΈΡ
ΠΊΠ°ΠΊ ΡΠΎΠΏΡΡΡΡΠ²ΡΡΡΠΈΠ΅ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡ ΠΈ ΡΠΎΡΡΠΎΡΠ½ΠΈΡ, Π° ΡΠ°ΠΊΠΆΠ΅ ΠΌΠ΅ΠΆΠ»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
Π²Π·Π°ΠΈΠΌΠΎΠ΄Π΅ΠΉΡΡΠ²ΠΈΠΉ. Π‘ ΡΡΠΈΡ
ΠΏΠΎΠ·ΠΈΡΠΈΠΉ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ½ΡΡ
ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ΠΎΠ² ΠΊ ΠΏΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈ ΠΏΡΠΎΡΠΈΠ»Π°ΠΊΡΠΈΠΊΠ΅ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΡΡΠΎΠ³Π΅Π½Π½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΠΎΡΠ°ΠΆΠ΅Π½ΠΈΠΉ Π²Π½ΡΡΡΠ΅Π½Π½ΠΈΡ
ΠΎΡΠ³Π°Π½ΠΎΠ² Ρ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΊΠ°ΠΊ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠ³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΡ
(ΡΠΆΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎ ΠΏΡΠΎΠ²ΠΎΠ΄ΡΡΡΡ), ΡΠ°ΠΊ ΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΊΠΈΠ½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΡ
(ΠΌΠΎΠ½ΠΈΡΠΎΡΠΈΠ½Π³ ΡΠ°Π²Π½ΠΎΠ²Π΅ΡΠ½ΡΡ
ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠ°ΡΠΈΠΉ Π»Π΅ΠΊΠ°ΡΡΡΠ² Π² Π±ΠΈΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΆΠΈΠ΄ΠΊΠΎΡΡΡΡ
, ΠΌΠ°Π»ΠΎΠΈΠ½Π²Π°Π·ΠΈΠ²Π½Π°Ρ ΠΎΡΠ΅Π½ΠΊΠ° Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠ΅ΡΠΌΠ΅Π½ΡΠ°ΡΠΈΠ²Π½ΡΡ
ΡΠΈΡΡΠ΅ΠΌ, ΠΈ ΠΏΡΠ΅ΠΆΠ΄Π΅ Π²ΡΠ΅Π³ΠΎ ΠΈΠ·ΠΎΡΠ΅ΡΠΌΠ΅Π½ΡΠΎΠ² ΡΠΈΡΠΎΡ
ΡΠΎΠΌΠ° Π -450) ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΉ, ΠΊΠΎΡΠΎΡΡΠ΅ Π±ΡΠ΄ΡΡ Π΄ΠΎΡΡΡΠΏΠ½Ρ Π²ΡΠ°ΡΠ°ΠΌ (Π² Ρ.Ρ. Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΠΈΠ½ΡΠΎΡΠΌΠ°ΡΠΈΠΎΠ½Π½ΡΡ
ΡΠ΅Ρ
Π½ΠΎΠ»ΠΎΠ³ΠΈΠΉ β Π·Π° ΡΡΠ΅Ρ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠΈ ΠΊΠΎΠΌΠΏΡΡΡΠ΅ΡΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΡ ΠΏΠΎΠ΄Π΄Π΅ΡΠΆΠΊΠΈ ΠΏΡΠΈΠ½ΡΡΠΈΡ ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠ΅ΡΠ΅Π½ΠΈΠΉ), ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΡ ΠΈΠΌ ΠΏΠ΅ΡΡΠΎΠ½Π°Π»ΠΈΠ·ΠΈΡΠΎΠ²Π°ΡΡ ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅ Π»Π΅ΠΊΠ°ΡΡΡΠ², ΡΠ²ΠΎΠ΄Ρ ΠΊ ΠΌΠΈΠ½ΠΈΠΌΡΠΌΡ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΠ΅ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΠ΅ ΡΠ΅Π°ΠΊΡΠΈΠΈ ΠΈ ΡΠ½ΠΈΠΆΠ°Ρ ΡΠ΅ΠΌ ΡΠ°ΠΌΡΠΌ ΠΈΠ½Π²Π°Π»ΠΈΠ΄ΠΈΠ·Π°ΡΠΈΡ ΠΈ ΡΠΌΠ΅ΡΡΠ½ΠΎΡΡΡ ΠΎΡ Π½ΠΈΡ
. Π’Π°ΠΊΠΈΠΌ ΠΎΠ±ΡΠ°Π·ΠΎΠΌ, Π°ΠΊΡΡΠ°Π»ΡΠ½ΡΠΌΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡΡΡΡ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ½ΡΠ΅ (ΡΠ°ΡΠΌΠ°ΠΊΠΎΠ³Π΅Π½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΠΊΠΈΠ½Π΅ΡΠΈΡΠ΅ΡΠΊΠΈΠ΅) ΠΏΠΎΠ΄Ρ
ΠΎΠ΄Ρ ΠΊ ΠΏΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΈ ΠΏΡΠΎΡΠΈΠ»Π°ΠΊΡΠΈΠΊΠ΅ (Π½Π° ΠΎΡΠ½ΠΎΠ²Π΅ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ Π°Π»Π³ΠΎΡΠΈΡΠΌΠΎΠ² Π²ΡΠ±ΠΎΡΠ° ΠΠ‘ ΠΈ ΠΈΡ
ΡΠ΅ΠΆΠΈΠΌΠΎΠ² Π΄ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ) ΡΡΡΠΎΠ³Π΅Π½Π½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΏΠΎΡΠ°ΠΆΠ΅Π½ΠΈΠΉ Π²Π½ΡΡΡΠ΅Π½Π½ΠΈΡ
ΠΎΡΠ³Π°Π½ΠΎΠ² Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΡΠΎΡΠΈΠ°Π»ΡΠ½ΠΎ Π·Π½Π°ΡΠΈΠΌΡΠΌΠΈ Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΡΠΌΠΈ
ΠΠ»ΠΈΡΠ½ΠΈΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠΈΠ·ΠΌΠ° CYP2D6*4 Π½Π° ΠΏΡΠΎΡΠΈΠ»Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½Π° Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²ΠΎΠΌ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½ΠΎΠΉ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡΡ
Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder, which adversely affects the prognosis of the course of both diseases. For the treatment of a depressive disorder, drugs from the group of tetracyclic antidepressants, of which mirtazapine is a representative, are used. Therapy with mirtazapine is associated with the risk of undesirable drug reactions and pharmacoresistance.
Aim: To study the effect of CYPD6 isoenzyme activity on the efficacy and safety of mirtazapine therapy in patients with depressive disorders comorbid with alcoholism.
Methods: The study was conducted on 109 Russian patients with a depressive disorder, comorbid with alcohol dependence. For the correction of depressive disorders within the framework of cyclothymia, mirtazapine was prescribed to patients at a dosage of 1545 mg/day. CYP2D6*4 genotyping (1846G A, rs3892097) was carried out using Real-time polymerase chain reaction with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of adverse drug reactions.
Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.8; 5.0] (p0.001), safety indicator, estimated on a UKU scale: (GG) 3.0 [3.0; 3.0], (GA) 4.0 [4.0; 5.0] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [0.8; 3.2] (p0.001), safety indicator, estimated on a UKU scale: (GG) 6.0 [6.0; 7.0], (GA) 8.5 [8.0; 10.0] (p0.001).
Conclusion: In this study, the effect of CYP2D6 gene polymorphism on the efficacy and safety of therapy with mirtazapine was demonstrated. Carrying a minor allele A is associated with an increased risk of adverse drug reactions, but improving performance profile performance.ΠΠ±ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠ΅. ΠΡΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠ΅ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠ΅ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°, ΡΠ°ΡΡΠΎ ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΠΎ ΡΠΎΡΠ΅ΡΠ°ΡΡΡΡ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½ΠΎΠΉ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡΡ, ΡΡΠΎ Π½Π΅Π³Π°ΡΠΈΠ²Π½ΠΎ ΡΠΊΠ°Π·ΡΠ²Π°Π΅ΡΡΡ Π½Π° ΠΏΡΠΎΠ³Π½ΠΎΠ·Π΅ ΡΠ΅ΡΠ΅Π½ΠΈΡ ΠΎΠ±ΠΎΠΈΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. ΠΠ»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΠΎΠ³ΠΎ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π° ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΡΡ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΠ΅ ΡΡΠ΅Π΄ΡΡΠ²Π° ΠΈΠ· Π³ΡΡΠΏΠΏΡ ΡΠ΅ΡΡΠ°ΡΠΈΠΊΠ»ΠΈΡΠ΅ΡΠΊΠΈΡ
Π°Π½ΡΠΈΠ΄Π΅ΠΏΡΠ΅ΡΡΠ°Π½ΡΠΎΠ², ΠΏΡΠ΅Π΄ΡΡΠ°Π²ΠΈΡΠ΅Π»Π΅ΠΌ ΠΊΠΎΡΠΎΡΠΎΠ³ΠΎ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½. Π’Π΅ΡΠ°ΠΏΠΈΡ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½ΠΎΠΌ ΡΠΎΠΏΡΡΠΆΠ΅Π½Π° Ρ ΡΠΈΡΠΊΠΎΠΌ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ ΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΠΎΡΡΠΈ.
Π¦Π΅Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ β ΠΎΡΠ΅Π½ΠΈΡΡ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠ½ΠΎΠ³ΠΎ ΠΌΠ°ΡΠΊΠ΅ΡΠ° CYPD6*4 Π½Π° ΠΏΡΠΎΡΠΈΠ»Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½ΠΎΠΌ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²ΠΎΠΌ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΠΈΠ·ΠΌΠΎΠΌ.
ΠΠ΅ΡΠΎΠ΄Ρ. ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π½Π° 109 ΡΡΡΡΠΊΠΈΡ
ΠΏΠ°ΡΠΈΠ΅Π½ΡΠ°Ρ
Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²ΠΎΠΌ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½ΠΎΠΉ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡΡ. ΠΠ°ΡΠΈΠ΅Π½ΡΠ°ΠΌ Ρ ΡΠ΅Π»ΡΡ ΠΊΠΎΡΡΠ΅ΠΊΡΠΈΠΈ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΡ
ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ² Π² ΡΠ°ΠΌΠΊΠ°Ρ
ΡΠΈΠΊΠ»ΠΎΡΠΈΠΌΠΈΠΈ Π±ΡΠ» Π½Π°Π·Π½Π°ΡΠ΅Π½ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½ Π² Π΄ΠΎΠ·ΠΈΡΠΎΠ²ΠΊΠ΅ 1545 ΠΌΠ³/ΡΡΡ. ΠΠ΅Π½ΠΎΡΠΈΠΏΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ CYP2D6*4 (1846GA, rs3892097) ΠΎΡΡΡΠ΅ΡΡΠ²Π»ΡΠ»ΠΎΡΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠ°Π·Π½ΠΎΠΉ ΡΠ΅ΠΏΠ½ΠΎΠΉ ΡΠ΅Π°ΠΊΡΠΈΠΈ Π² ΡΠ΅ΠΆΠΈΠΌΠ΅ ΡΠ΅Π°Π»ΡΠ½ΠΎΠ³ΠΎ Π²ΡΠ΅ΠΌΠ΅Π½ΠΈ Ρ Π°Π»Π»Π΅Π»ΡΡΠΏΠ΅ΡΠΈΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π³ΠΈΠ±ΡΠΈΠ΄ΠΈΠ·Π°ΡΠΈΠ΅ΠΉ. ΠΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΡ ΠΎΡΠ΅Π½ΠΈΠ²Π°Π»ΠΈ Ρ ΠΏΠΎΠΌΠΎΡΡΡ Π²Π°Π»ΠΈΠ΄ΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΠΏΡΠΈΡ
ΠΎΠΌΠ΅ΡΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΊΠ°Π» ΠΈ ΡΠΊΠ°Π»Ρ ΠΎΡΠ΅Π½ΠΊΠΈ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΡΡΠΈ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ. Π 9-ΠΌΡ Π΄Π½Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΡΡΡ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΠΎΠΉ ΡΠΈΠΌΠΏΡΠΎΠΌΠ°ΡΠΈΠΊΠΈ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ HAMD ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΠΎ ΠΎΡΠ»ΠΈΡΠ°Π»Π°ΡΡ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΡΠ°Π·Π½ΡΠΌΠΈ Π³Π΅Π½ΠΎΡΠΈΠΏΠ°ΠΌΠΈ: (GG) 7,0 [6,0; 8,0], (GA) 4,0 [3,8; 5,0] (p0,001), ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ, ΠΎΡΠ΅Π½Π΅Π½Π½ΡΠΉ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ UKU: (GG) 3,0 [3,0; 3,0], (GA) 4,0 [4,0; 5,0] (p0,001). ΠΠ°Π»ΠΈΡΠΈΠ΅ ΡΠ°Π·Π»ΠΈΡΠΈΠΉ ΡΠΎΡ
ΡΠ°Π½ΡΠ»ΠΎΡΡ ΠΈ Π½Π° 16-ΠΉ Π΄Π΅Π½Ρ: (GG) 5,0 [3,0; 6,0], (GA) 1,5 [0,8; 3,2] (p0,001), ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ, ΠΎΡΠ΅Π½Π΅Π½Π½ΡΠΉ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ UKU: (GG) 6,0 [6,0; 7,0], (GA) 8,5 [8,0; 10,0] (p0,001).
ΠΠ°ΠΊΠ»ΡΡΠ΅Π½ΠΈΠ΅. ΠΠΎ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π±ΡΠ»ΠΎ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΠΈΡΠΎΠ²Π°Π½ΠΎ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠ½ΠΎΠ³ΠΎ ΠΌΠ°ΡΠΊΠ΅ΡΠ° CYP2D6*4 Π½Π° ΠΏΡΠΎΡΠΈΠ»Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΠΌΠΈΡΡΠ°Π·Π°ΠΏΠΈΠ½ΠΎΠΌ. ΠΠΎΡΠΈΡΠ΅Π»ΡΡΡΠ²ΠΎ ΠΌΠΈΠ½ΠΎΡΠ½ΠΎΠ³ΠΎ Π°Π»Π»Π΅Π»Ρ A ΡΠΎΠΏΡΡΠΆΠ΅Π½ΠΎ Ρ ΠΏΠΎΠ²ΡΡΠ΅Π½Π½ΡΠΌ ΡΠΈΡΠΊΠΎΠΌ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ, Π½ΠΎ ΡΠ»ΡΡΡΠ΅Π½ΠΈΠ΅ΠΌ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ΠΉ ΠΏΡΠΎΡΠΈΠ»Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ
ΠΠ»ΠΈΡΠ½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ CYP2D6 Π½Π° ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΡ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½Π° Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌΠΈ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°ΠΌΠΈ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌΠΈ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½ΠΎΠΉ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡΡ
Background: Alcohol dependence is often combined with affective disorders, in particular, depressive disorder (DD), which worsens adversely affects the prognosis of the course of both diseases and their outcomes. For the treatment of DD, drugs from the group of selective serotonin reuptake inhibitors, whose representative is fluvoxamine, are used. Fluvoxamine therapy is often associated with a risk of development is shown to be ineffective, and a part of patients develop dose-dependent adverse drug reactions (ADR) and pharmacoresistance.Objective: To study the effects of CYPD6 isoenzyme activity on the efficacy and safety of fluvoxamine therapy in patients with depressive disorders, comorbid with alcoholism.Methods: The study was conducted on 117 Russian patients with DD, alcohol-dependent comorbid. For the purpose of correction of depressive disorders within the framework of cyclothymia, fluvoxamine (Fevarin) was administered to patients at a dosage of 50β150 mg/day. Genotyping was carried out by the method of polymerase chain reaction in Real-time mode with allele-specific hybridization. Efficacy and safety were assessed using validated psychometric scales and an assessment of the severity of ADR. To evaluate the activity of CYP2D6, the method of high performance liquid chromatography with mass spectrometry was used to measure the urinary content of the endogenous substrate of this isoenzyme and its metabolite, the ratio of 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline.Results: By the 9th day of the study, the severity of depressive symptoms on the HAMD scale was statistically significantly different in patients with different genotypes: (GG) 7.0 [6.0; 8.0], (GA) 4.0 [3.0; 5.0] (p0.001); safety indicator, estimated on a UKU scale: 3.0 [2.0; 4.0], (GA) 4.0 [4.0; 4.2] (p0.001). The presence of differences persisted on the 16th day: (GG) 5.0 [3.0; 6.0], (GA) 1.5 [1.0; 3.0] (p0.001); safety indicator, estimated on a UKU scale: (GG) 9.0 [9.0; 10.0], (GA) 6.0 [6.0; 7.0] (p0.001). The calculation of the correlation coefficients between the difference in the number of scores on psychometric scales and the metabolic ratio showed a statistically significant inverse correlation of the average power degree between the efficiency index estimated by the HAMD scale (r=-0.467, p0.05). There was no connection with the difference on the UKU scale (r=0.173, p0.05).Conclusion: In a study of a group of 117 patients with DD, comorbid with alcohol dependence, the effect of CYP2D6 activity, estimated by the ratio of the endogenous substrate concentrations of pinolin and its metabolite 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline, on the efficacy of fluvoxamine therapy. This effect was also shown using the results of genotyping. The results of genotyping also showed the existence of a difference in the safety index in patients with different genotypes from the polymorphic marker CYP2D6 1846GA.ΠΠ±ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠ΅. ΠΠ»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½Π°Ρ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡ ΡΠ°ΡΡΠΎ ΡΠΎΡΠ΅ΡΠ°Π΅ΡΡΡ Ρ Π°ΡΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΌΠΈ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°ΠΌΠΈ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²ΠΎΠΌ, ΡΡΠΎ ΠΎΡΡΠΈΡΠ°ΡΠ΅Π»ΡΠ½ΠΎ ΡΠΊΠ°Π·ΡΠ²Π°Π΅ΡΡΡ Π½Π° ΠΏΡΠΎΠ³Π½ΠΎΠ·Π΅ ΡΠ΅ΡΠ΅Π½ΠΈΡ ΠΎΠ±ΠΎΠΈΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. ΠΠ»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΠΎΠ³ΠΎ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π° ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΡΡ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΠ΅ ΡΡΠ΅Π΄ΡΡΠ²Π° ΠΈΠ· Π³ΡΡΠΏΠΏΡ ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΡΡ
ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠΎΠ² ΠΎΠ±ΡΠ°ΡΠ½ΠΎΠ³ΠΎ Π·Π°Ρ
Π²Π°ΡΠ° ΡΠ΅ΡΠΎΡΠΎΠ½ΠΈΠ½Π°, ΠΏΡΠ΅Π΄ΡΡΠ°Π²ΠΈΡΠ΅Π»Π΅ΠΌ ΠΊΠΎΡΠΎΡΠΎΠ³ΠΎ ΡΠ²Π»ΡΠ΅ΡΡΡ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½. Π’Π΅ΡΠ°ΠΏΠΈΡ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½ΠΎΠΌ ΡΠΎΠΏΡΡΠΆΠ΅Π½Π° Ρ ΡΠΈΡΠΊΠΎΠΌ ΡΠ°Π·Π²ΠΈΡΠΈΡ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ ΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΠΎΡΡΠΈ. Π Π±ΠΎΠ»Π΅Π΅ ΡΠ°Π½Π½ΠΈΡ
ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡΡ
Π±ΡΠ»ΠΎ ΠΏΠΎΠΊΠ°Π·Π°Π½ΠΎ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΠ΅ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠΈΠ·ΠΌΠ° Π³Π΅Π½Π° CYP2D6, ΠΊΠΎΠ΄ΠΈΡΡΡΡΠ΅Π³ΠΎ ΠΎΠ΄Π½ΠΎΠΈΠΌΠ΅Π½Π½ΡΠΉ ΠΈΠ·ΠΎΡΠ΅ΡΠΌΠ΅Π½Ρ, Π½Π° ΡΠ°ΡΡΠΎΡΡ ΠΈ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΡΡΡ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½Π°.Π¦Π΅Π»Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ β ΠΈΠ·ΡΡΠΈΡΡ Π²Π»ΠΈΡΠ½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΈΠ·ΠΎΡΠ΅ΡΠΌΠ΅Π½ΡΠ° CYPD6 Π½Π° ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΡ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½ΠΎΠΌ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌΠΈ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°ΠΌΠΈ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌΠΈ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΠΈΠ·ΠΌΠΎΠΌ.ΠΠ΅ΡΠΎΠ΄Ρ. ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π½Π° 117 ΡΡΡΡΠΊΠΈΡ
ΠΏΠ°ΡΠΈΠ΅Π½ΡΠ°Ρ
Ρ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΠΌΠΈ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²Π°ΠΌΠΈ, ΠΊΠΎΠΌΠΎΡΠ±ΠΈΠ΄Π½ΡΠΌΠΈ Ρ Π°Π»ΠΊΠΎΠ³ΠΎΠ»ΡΠ½ΠΎΠΉ Π·Π°Π²ΠΈΡΠΈΠΌΠΎΡΡΡΡ. ΠΠ°ΡΠΈΠ΅Π½ΡΠ°ΠΌ Ρ ΡΠ΅Π»ΡΡ ΠΊΠΎΡΡΠ΅ΠΊΡΠΈΠΈ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΡΡ
ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ² Π² ΡΠ°ΠΌΠΊΠ°Ρ
ΡΠΈΠΊΠ»ΠΎΡΠΈΠΌΠΈΠΈ Π±ΡΠ» Π½Π°Π·Π½Π°ΡΠ΅Π½ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½ Π² Π΄ΠΎΠ·ΠΈΡΠΎΠ²ΠΊΠ΅ 50β150 ΠΌΠ³/ΡΡΡ. ΠΠ΅Π½ΠΎΡΠΈΠΏΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ CYP2D6*4 (1846GA, rs3892097) ΠΎΡΡΡΠ΅ΡΡΠ²Π»ΡΠ»ΠΎΡΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠΌ ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠ°Π·Π½ΠΎΠΉ ΡΠ΅ΠΏΠ½ΠΎΠΉ ΡΠ΅Π°ΠΊΡΠΈΠΈ Π² ΡΠ΅ΠΆΠΈΠΌΠ΅ ΡΠ΅Π°Π»ΡΠ½ΠΎΠ³ΠΎ Π²ΡΠ΅ΠΌΠ΅Π½ΠΈ Ρ Π°Π»Π»Π΅Π»ΡΡΠΏΠ΅ΡΠΈΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π³ΠΈΠ±ΡΠΈΠ΄ΠΈΠ·Π°ΡΠΈΠ΅ΠΉ. ΠΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΡ ΠΎΡΠ΅Π½ΠΈΠ²Π°Π»ΠΈ Ρ ΠΏΠΎΠΌΠΎΡΡΡ Π²Π°Π»ΠΈΠ΄ΠΈΠ·ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΠΏΡΠΈΡ
ΠΎΠΌΠ΅ΡΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΊΠ°Π» ΠΈ ΡΠΊΠ°Π»Ρ ΠΎΡΠ΅Π½ΠΊΠΈ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΡΡΠΈ Π½Π΅ΠΆΠ΅Π»Π°ΡΠ΅Π»ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΡΠ΅Π°ΠΊΡΠΈΠΉ. ΠΠ»Ρ ΠΎΡΠ΅Π½ΠΊΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ CYP2D6 ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ ΠΌΠ΅ΡΠΎΠ΄ Π²ΡΡΠΎΠΊΠΎΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠΉ ΠΆΠΈΠ΄ΠΊΠΎΡΡΠ½ΠΎΠΉ Ρ
ΡΠΎΠΌΠ°ΡΠΎΠ³ΡΠ°ΡΠΈΠΈ Ρ ΠΌΠ°ΡΡ-ΡΠΏΠ΅ΠΊΡΡΠΎΠΌΠ΅ΡΡΠΈΠ΅ΠΉ ΠΏΠΎ ΡΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΈΡ Π² ΠΌΠΎΡΠ΅ ΡΠ½Π΄ΠΎΠ³Π΅Π½Π½ΠΎΠ³ΠΎ ΡΡΠ±ΡΡΡΠ°ΡΠ° Π΄Π°Π½Π½ΠΎΠ³ΠΎ ΠΈΠ·ΠΎΡΠ΅ΡΠΌΠ΅Π½ΡΠ° ΠΈ Π΅Π³ΠΎ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ° β ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΠ΅ 6-Π³ΠΈΠ΄ΡΠΎΠΊΡΠΈ-1,2,3,4-ΡΠ΅ΡΡΠ°Π³ΠΈΠ΄ΡΠΎ-Π±Π΅ΡΠ°-ΠΊΠ°ΡΠ±ΠΎΠ»ΠΈΠ½Π°.Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ. Π 9-ΠΌΡ Π΄Π½Ρ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΠΎΡΡΡ Π΄Π΅ΠΏΡΠ΅ΡΡΠΈΠ²Π½ΠΎΠΉ ΡΠΈΠΌΠΏΡΠΎΠΌΠ°ΡΠΈΠΊΠΈ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ HAMD ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΠΎ ΠΎΡΠ»ΠΈΡΠ°Π»Π°ΡΡ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΡΠ°Π·Π½ΡΠΌΠΈ Π³Π΅Π½ΠΎΡΠΈΠΏΠ°ΠΌΠΈ: (GG) 7,0 [6,0; 8,0], (GA) 4,0 [3,0; 5,0] (p0,001); ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ, ΠΎΡΠ΅Π½Π΅Π½Π½ΡΠΉ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ UKU: 3,0 [2,0; 4,0], (GA) 4,0 [4,0; 4,2] (p0,001). ΠΠ°Π»ΠΈΡΠΈΠ΅ ΡΠ°Π·Π»ΠΈΡΠΈΠΉ ΡΠΎΡ
ΡΠ°Π½ΡΠ»ΠΎΡΡ ΠΈ Π½Π° 16-ΠΉ Π΄Π΅Π½Ρ: (GG) 5,0 [3,0; 6,0], (GA) 1,5 [1,0; 3,0] (p0,001); ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ, ΠΎΡΠ΅Π½Π΅Π½Π½ΡΠΉ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ UKU: (GG) 9,0 [9,0; 10,0], (GA) 6,0 [6,0; 7,0] (p0,001). Π Π°ΡΡΠ΅Ρ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ΠΉ ΠΊΠΎΡΡΡΠΈΡΠΈΠ΅Π½ΡΠΎΠ² ΠΊΠΎΡΡΠ΅Π»ΡΡΠΈΠΈ ΠΌΠ΅ΠΆΠ΄Ρ ΡΠ°Π·Π½ΠΈΡΠ΅ΠΉ Π² ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π΅ Π±Π°Π»Π»ΠΎΠ² ΠΏΠΎ ΠΏΡΠΈΡ
ΠΎΠΌΠ΅ΡΡΠΈΡΠ΅ΡΠΊΠΈΠΌ ΡΠΊΠ°Π»Π°ΠΌ ΠΈ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΈΠΌ ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΠ΅ΠΌ ΠΏΠΎΠΊΠ°Π·Π°Π» Π½Π°Π»ΠΈΡΠΈΠ΅ ΡΡΠ°ΡΠΈΡΡΠΈΡΠ΅ΡΠΊΠΈ Π·Π½Π°ΡΠΈΠΌΠΎΠΉ ΠΎΠ±ΡΠ°ΡΠ½ΠΎΠΉ ΠΊΠΎΡΡΠ΅Π»ΡΡΠΈΠΈ ΡΡΠ΅Π΄Π½Π΅ΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ ΡΠΈΠ»Ρ ΠΌΠ΅ΠΆΠ΄Ρ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Π΅ΠΌ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ, ΠΎΡΠ΅Π½Π΅Π½Π½ΠΎΠΉ Ρ ΠΏΠΎΠΌΠΎΡΡΡ ΡΠΊΠ°Π»Ρ HAMD (r=-0,467, p0,05). Π‘Π²ΡΠ·Ρ Ρ ΡΠ°Π·Π½ΠΈΡΠ΅ΠΉ ΠΏΠΎ ΡΠΊΠ°Π»Π΅ UKU ΠΎΡΡΡΡΡΡΠ²ΠΎΠ²Π°Π»Π° (r=0,173, p0,05).ΠΠ°ΠΊΠ»ΡΡΠ΅Π½ΠΈΠ΅. Π Π΄Π°Π½Π½ΠΎΠΌ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΈ Π±ΡΠ»ΠΎ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΠΈΡΠΎΠ²Π°Π½ΠΎ Π²Π»ΠΈΡΠ½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ CYP2D6, ΠΎΡΠ΅Π½Π΅Π½Π½ΠΎΠΉ ΠΏΠΎ ΠΎΡΠ½ΠΎΡΠ΅Π½ΠΈΡ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠ°ΡΠΈΠΉ ΡΠ½Π΄ΠΎΠ³Π΅Π½Π½ΠΎΠ³ΠΎ ΡΡΠ±ΡΡΡΠ°ΡΠ° ΠΏΠΈΠ½ΠΎΠ»ΠΈΠ½Π° ΠΈ Π΅Π³ΠΎ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ° 6-Π³ΠΈΠ΄ΡΠΎΠΊΡΠΈ-1,2,3,4-ΡΠ΅ΡΡΠ°Π³ΠΈΠ΄ΡΠΎ-Π±Π΅ΡΠ°-ΠΊΠ°ΡΠ±ΠΎΠ»ΠΈΠ½Π°, Π½Π° ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½ΠΎΠΌ. ΠΠΎΠ²ΡΡΠ΅Π½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ CYP2D6 ΡΠ½ΠΈΠΆΠ°Π΅Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ ΡΠ»ΡΠ²ΠΎΠΊΡΠ°ΠΌΠΈΠ½ΠΎΠΌ. ΠΠ»ΠΈΡΠ½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ CYP2D6 Π½Π° Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΡ ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π΅Π½ΠΎ Π½Π΅ Π±ΡΠ»ΠΎ. Π’Π΅ΠΌ Π½Π΅ ΠΌΠ΅Π½Π΅Π΅ ΠΎΠ±Π½Π°ΡΡΠΆΠ΅Π½ΠΎ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΠΏΠΎΠ»ΠΈΠΌΠΎΡΡΠΈΠ·ΠΌΠ° Π³Π΅Π½Π° CYP2D6 Π½Π° ΠΏΡΠΎΡΠΈΠ»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ
Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users
Publisher Copyright: Β© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and TherapeuticsThis study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.Peer reviewe
The CES1 Gene rs2244613 minor allele impact on the safety profile of dabigatran etexilate: Meta-analysis [ΠΠ»ΠΈΡΠ½ΠΈΠ΅ Π½ΠΎΡΠΈΡΠ΅Π»ΡΡΡΠ²Π° ΠΌΠΈΠ½ΠΎΡΠ½ΠΎΠΉ Π°Π»Π»Π΅Π»ΠΈ rs2244613 Π³Π΅Π½Π° CES1 Π½Π° ΠΏΡΠΎΡΠΈΠ»Ρ Π±Π΅Π·ΠΎΠΏΠ°ΡΠ½ΠΎΡΡΠΈ Π΄Π°Π±ΠΈΠ³Π°ΡΡΠ°Π½Π° ΡΡΠ΅ΠΊΡΠΈΠ»Π°ΡΠ°: ΠΌΠ΅ΡΠ°-Π°Π½Π°Π»ΠΈΠ·]
Aim. A meta-analysis of studies on the CES1 gene c.1168-33A>C polymorphism (rs2244613) carriage influence on the equilibrium concentration and the risk of bleeding during dabigatran taking. Material and methods. The search was carried out in the Russian Science Citation Index, Google Academy, Medline PubMed, Embase databases. The meta-analysis included patients who according to the indications (atrial fibrillation, stroke, joint orthopedic surgery) were prescribed dabigatran in various doses. The association was identified in rs2244613 allele C carriers (genotypes AC and CC) and non-carriers (genotype AA). Quantitative synthesis was performed using OpenMetaAnalyst software. In statistical analysis the fixed effects model was used to estimate the influence of the allele C carriage on the any bleeding frequency and the random effects model was used to estimate the influence on the equilibrium plasma concentration level of dabigatran. The homogeneity of the analyzed studies was verified by Cochrane Q-test. Results. The analysis resulted in selection of 5 works matching all meta-analysis inclusion/exclusion criteria. All selected works included 2030 patients in total. The carriage of the rs2246613 allele C was associated with reduction of risk of any bleeding during dabigatran taking (risk ratio [RR] 0.732, 95% confidence interval [CI] 0.629-0.851; p<0.001). The heterogeneity test did not reveal any reliable differences between the study results (Q=2.183; p=0.535). The level of equilibrium residual concentration of dabigatran was not statistically significant lower for the carriers of C allele of the rs2244613 (mean difference -69.324, 95%CI -236.687-98.039; p=0.417). This might be related to the small sample size and the number of studies included in the meta-analysis. The heterogeneity test did not reveal statistically significant differences between studies (Q=0.388; I2=0%, p=0.534). Conclusion. The carriage of minor C allelic variant of rs2244613 reduces the risk of any bleeding during dabigatran taking, however, no significant association with decrease in dabigatran concentration was found. Β© 2020 Stolichnaya Izdatelskaya Kompaniya. All rights reserved