RU2642284C1 - Method for selection of perindopril dosage forpatients with ischemic heart disease on background of arterial hypertension - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: polymorphism of the AGTR2 rs1403543 gene is determined. In case of detection of a homozygous version of GG, perindopril dose is 1.3 times lower than in individuals with allele version AA.

EFFECT: increased therapy effectiveness and safety.

4 tbl, 3 ex

Description

The invention relates to the field of cardiology, in particular to the treatment of coronary heart disease and arterial hypertension.

Cardiovascular disease (CVD), mainly coronary heart disease (CHD), remains the main cause of mortality and disability in Russia and other industrialized countries (Oganov R.G. Vascular comorbidity: general approaches to prevention and treatment // Oganov Rafael Geghamovich (2015). Vascular comorbidity: general approaches to prevention and treatment. Rational pharmacotherapy in cardiology, 2015; 1: 4-7).

ACE inhibitors are widely used in medical practice, in particular in the treatment of various forms of coronary heart disease and arterial hypertension (Lupanov V.P. Angiotensin-converting enzyme inhibitors in the treatment and prognosis of life of patients with coronary artery disease and chronic heart failure. Focus on ramipril // Russian Medical Journal, 2009; 8: 582).

It is known that the pharmacological response in patients with the same disease will not be the same, but will depend on the genotype of each individual. Currently, the concept of personalization of those drugs that were previously considered universal is gaining momentum (Scherbakova N.V., Ershova A.I., Suvorova A.A. et al. Pharmacogenetic testing capabilities in cardiology based on exogenous sequencing data // Rational pharmacotherapy in cardilogy, 2014; 6: 646-650).

The genetic characteristics of patients associated with changes in the pharmacological response are determined using pharmacogenetic testing (Scherbakova N.V., Meshkov A.N., Boytsov S.A. Application of the exome sequencing method for diagnosing predisposition to complex diseases in preventive medicine // Cardiovascular therapy and prevention, 2013; 6: 24-28), which is one of the applied tools of personalized medicine and the most promising for clinical practice (Sychev D.A., Kazakov R.E., Otdelenov V .A. Applied aspects of the use of pharmacogenetic testing to personalize the use of oral anticoagulants in Russian conditions // Rational Pharmacotherapy in Cardiology, 2013; 5: 525-531).

There is a method of choosing the dosage of drugs from the group of statins to determine the carriage of the allelic variant of the SLCO1B1 * 5 gene. If heterozygous (genotype c.521TC) or homozygous (genotype 521CC) carriers of the allelic variant SLCO1B1 * 5 (s.521T> C) are detected, the maximum dose of statins should be lower compared to carriers of the C.521TT genotype (“wild” type) ( Sychev D.A. Pharmacogenetic testing: clinical interpretation of the results / D.A. Sychev // - M .: GEOTAR-MEDIA, 2011).

A known method of selecting the dosage of metoprolol beta-blocker according to the definition of the allelic variant of the CYP2D6 gene. If homozygous carriage of “slow” allelic variants CYP2D6 * 3, CYP2D6 * 4, CYP2D6 * 5, CYP2D6 * 6, CYP2D6 * 7, CYP2D6 * 9, CYP2D6 * 10, CYP2D6 * 41 is detected: the maximum dose of metoprolol should not exceed 50 mg / day If heterozygous carriage of "slow" allelic variants CYP2D6 * 3, CYP2D6 * 4, CYP2D6 * 5, CYP2D6 * 6, CYP2D6 * 7, CYP2D6 * 9, CYP2D6 * 10, CYP2D6 * 41 is detected: the maximum dose of metoprolol should not exceed 100 mg / day When identifying the CYP2D6 * 1 / * 1 genotype, metoprolol is used in doses prescribed in the instructions for medical use (Sychev D.A. Pharmacogenetic testing: clinical interpretation of the results / D.A.Sychev // - M .: GEOTAR-MEDIA, 2011) .

The prototype of this method is a method for determining the effective therapeutic dose of an antiepileptic drug and the risk of side effects, including the collection of biological material, the polymerase chain reaction of the candidate genes PPARy (Pro12Ala), PCKS1 (Ser690Thr), FABP2 (Ala54Thr), MDR1 (C3435T), SCN1A (SCN1IVS5N (5G> A), Glut9 (Val253Ile), URAT1 (-788 T> A), SERT (5HTTLPR), TPH2 (rs10748185), UGT2B7 (C802T), subsequent analysis of their allelic variants and by matching the revealed allelic polymorph data on its effect on the effective therapeutic dose and has arisen and side effects of the effective therapeutic doses of the antiepileptic drug and determining the risk of side effects (Burd S., Aksenov MG, Cricova EV № RU Patent 2574204).

The aim of the proposed method for choosing the dosage of perindopril in patients with coronary heart disease with hypertension is to increase the effectiveness and safety of pharmacotherapy.

This goal is achieved in that patients with coronary artery disease on the background of arterial hypertension to achieve a sufficient hypotensive effect when prescribing perindopril are recommended to determine the AGTR2 rs1403543 gene polymorphism. In this case, if a homozygous variant of GG is detected, the dosage of perindopril is 1.3 times lower than in individuals with an allelic variant of AA.

The novelty of the proposed method lies in the fact that the selection of dosages of perindopril is carried out taking into account genetic testing to determine the allelic variant of the AGTR2 rs1403543 gene, responsible for the development of this pathology.

Technical solutions that have features that match the distinguishing features of our proposed method are not identified, which allows us to conclude that the proposed method meets the criterion of "inventive step".

The proposed method is as follows.

First, peripheral blood sampling is performed from the patient. Then, the patient’s DNA is isolated from the blood by polymerase chain reaction (PCR). To obtain DNA from the analyzed material, a set of reagents for isolation is used (Syntol company). To assess the amount of DNA extracted, a set of reagents for PCR amplification of human genomic DNA in real time (CME) manufactured by Syntol is used.

Next, using a complex of reagents intended for use with detecting amplifiers (Syntol company), the AGTR2 rs1403543 gene polymorphism is determined.

After that, the interpretation of the results is performed. When identifying an allelic variant of the GG of the AGTR2 rs1403543 gene, dosages of perindopril are used 1.3 times lower than in individuals with an allelic variant of AA.

Clinical studies of the method were performed on 62 patients with various forms of coronary heart disease: myocardial infarction, unstable and stable forms of angina pectoris against the background of arterial hypertension.

The results revealed that in patients with a homozygous allelic variant GG, the dosage of perindopril is 1.3 times lower than homozygotes for the polymorphic variant AA (Table 1).

Blood pressure in patients divided into groups according to genotype did not differ either before perindopril or after it (Table 2).

As a result of the correlation analysis, it was found that the presence of the polymorphic A allele of the AGTR2 gene is associated (a correlation coefficient of 0.34 - moderate correlation) with higher dosages of perindopril AFP (Table 3).

Regression analysis revealed that the presence of the polymorphic allele A is associated with higher dosages of perindopril (Table 4).

The proposed method is illustrated by the following examples.

Example 1

Patient K., 64, was admitted to the cardiology department with complaints of pain behind the sternum periodically occurring during physical exertion, and a periodic increase in blood pressure to 160/90 mm Hg. Art. The patient was diagnosed with the main one: coronary heart disease: stable angina pectoris. Background: hypertension of 2 degrees, 3 stages, very high risk. Blood pressure at admission 162/89 mm RT. Art.

First, the patient was prescribed perindopril at a dosage of 5 mg / day. After 3 days, blood pressure was 149/85 mm Hg. Art. The patient underwent genetic analysis, which revealed the carrier of the AGTR2 gene polymorphism in the form of homozygous AA, which requires the appointment of a larger dosage of perindopril to achieve the target figures for blood pressure.

The dosage of perindopril was increased to 10 mg / day. After 3 days, blood pressure was 125/83 mm RT. Art. and remained within normal values until discharge from the hospital.

Example 2

Patient T., 55 years old, was admitted to the cardiology department with complaints of pain behind the sternum periodically occurring during physical exertion, and episodes of periodic increase in blood pressure up to 170/90 mm Hg. Art. The patient was diagnosed with the main one: coronary heart disease: stable angina pectoris. Background: hypertension of 2 degrees, 3 stages, very high risk. Blood pressure at admission 164/92 mm RT. Art.

The patient is prescribed perindopril at a dosage of 5 mg per day. After 3 days, blood pressure was 123/85 mm RT. Art. The patient underwent genetic analysis, which revealed an allelic variant of the AGTR2 gene in the form of GG homozygos, which requires the appointment of a lower dosage of perindopril to achieve the target figures for blood pressure than for individuals with an allelic variant of AA. The patient did not change the dosage of perindopril 5 mg and after 10 days blood pressure remained within normal values.

Example 3

Patient P., 64, was admitted to the cardiology department with complaints of periodically increasing blood pressure up to 165/95 mm RT. Art. The main diagnosis was made: Hypertension 2 degrees, 2 stages, high risk. Blood pressure at admission 159/94 mm RT. Art. The patient was prescribed perindopril at a dosage of 4 mg per day. After 3 days, blood pressure was 150/86 mm RT. Art. A genetic analysis was performed that revealed the carrier of the polymorphism of the AGTR2 gene in the form of homozygous AA, which requires the appointment of a larger dosage of perindopril to achieve the target blood pressure figures.

The dosage was increased to 8 mg / day and after 3 days the blood pressure was 122/84 mm RT. Art. Normal blood pressure values remained until discharge from the hospital.

The proposed method is used to select the dosage of perindopril in patients with coronary heart disease on the background of arterial hypertension in the Institution "Clinical Highway Hospital at st. Yaroslavl Russian Railways.

Claims (1)

The method of choosing the dosage of perindopril in patients with coronary heart disease on the background of arterial hypertension, which consists in determining the gene polymorphism in the patient’s peripheral blood, characterized in that the AGTR2 rs1403543 gene polymorphism is determined and, when a homozygous GG variant is detected, the dosage of perindopril is 1.3 times lower, than in individuals with a homozygous allelic variant of AA.