RU2726071C1 - Method of treatment of isolated systolic arterial hypertension of 1 degree in patients in early period of old and senile age - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to therapy, cardiology and clinical pharmacology, and can be used for treating isolated degree 1 systolic arterial hypertension (ISAH) in patients of early period of old age - 65–74 years and senile age - older than 75 years. In all patients with ISAH 1 degree of the above age, molecular diagnostics of blood plasma is performed and the level of expression of cathepsin G, myeloperoxidase, induced hypoxia Ia, hyaluronidase, kininogen-1, pyruvate kinase and subunit of alpha ATP-synthase. In the senile age, the level of expression of apolipoprotein D, a transforming growth factor beta-1, fibulin-5 is additionally determined. If observing the presence of a level of expression of cathepsin G equal to 3.5 ng/ml or more, myeloperoxidase, equal to 23 Un/ml or more, hypoxia of the induced factor Ia equal to 280 pg/ml or more, hyaluronidase equal to 9 mE/l or more, kininogen-1 equal to 85 ng/ml or more, pyruvate kinase equal to 10 Un/ml or more, and subunit of alpha ATP-synthase equal to 60 pg/ml or more, apolipoprotein D, equal to or greater than 30 ng/ml, transforming growth factor beta-1 equal to 900 pg/ml or more, fibulin-5 equal to 250 pg/ml or more, therapy is ensured by prescribing a combination of the blocker to the angiotensin II receptor and the slow calcium channel blocker.EFFECT: method provides reducing the dose of hypotensive medicines, increasing the effectiveness and safety of the treatment while reducing the economic costs of the pharmacotherapy by using the antihypertensive drugs taking into account the molecular profile of the blood plasma in each patient.1 cl, 2 ex

Description

The invention relates to medicine, namely to therapy, cardiology and clinical pharmacology, and can be used for the diagnosis and treatment of patients in the early period of old age and senile age with isolated systolic hypertension (ISAG) of 1 degree.

Known RF patent No. 2264163 "Method for the differential diagnosis of variants of the course of arterial hypertension", IPC AB 5/02, publ. November 20, 2005, in which the variants of the course of arterial hypertension (AH) are judged by the specific values of the measured parameters in a clinical and instrumental study: the total peripheral vascular resistance (OPSS), cardiac index (SI), stroke index (UI), left myocardial mass are measured ventricle (LVM), final diastolic volume (BWW), final systolic volume (CSR) and ejection fraction (EF). The method allows to increase the accuracy of the differential diagnosis of variants of the course of hypertension according to the predominant lesion of target organs: with a value of OPSS = 2123 dyn⋅s 2m ² or more, SI = 3180 ml⋅m ² or more, UI = 42.8 ml⋅m ² and more, CML = 194.3 g or more, BWW = 140.2-150.0 ml, KSO = 55.8-58.0 ml, PV = 56.8% or more, is diagnosed with ISAG; at a value OPSS = 1960-2082 din⋅s⋅m ^2, SR = 2924 ml⋅m ² or less, MI = 30.9 ml⋅m ² or less, MMLV = 184.4 g or less, CSR = 52.8 ml or less, BWW = 138.2 ml or less, PV = 51.0-52.2% diagnose cerebro-ischemic hypertension; when the value of BWW = 150.8 ml or more, and KSO = 58.4 ml or more and at lower CML = 185-187 g, PV = 50.7% or less and OPSS = 1954.2 dyn ² or less, SI = 2930-3057 ml⋅m ² , SI = 32.0-41.9 ml⋅m ² diagnose coronary ischemic hypertension.

However, the known method for differential diagnosis of options for the course of hypertension does not provide for the analysis of the results of standard laboratory tests; analysis of differences in the results of clinical and instrumental methods of research in hypertension, including ISAG, depending on age, for example, an early period of old age and senile age; the invention does not present the molecular phenotypes of blood plasma of each AH variant, which determine the results of the clinical and instrumental research methods proposed for the diagnosis.

Also known is the patent of the Russian Federation No. 2571284 “Pharmaceutical composition and method for the treatment of hypertension”, IPC A61K 31/485, A61P 9/10, publ. 12/20/2015, which presents a pharmaceutical composition and method for treating AH, the essence of which is that a pharmaceutical composition for treating AH in a subject includes an effective amount of dextromethorphan, an effective amount of a calcium channel blocker and a pharmaceutically acceptable carrier, wherein the calcium channel blocker amlodipine. The method of treatment involves the use of dextromethorphan to obtain a dosage form for the treatment of hypertension in a subject, where the dosage form further includes a calcium channel blocker, which is amlodipine.

However, the known method does not imply a preliminary assessment of the effectiveness and safety of other standard combined antihypertensive treatment regimens, including beta-blockers, diuretics, ACE inhibitors, angiotensin II receptor blockers before prescribing the original pharmaceutical composition; assessment of the effectiveness and safety of the original pharmaceutical composition in a clinical trial in humans based on standard methods for the diagnosis of hypertension; identifying a specific diagnostic complex of biomarkers in the blood in groups of patients in the early period of old age and senile age with ISAH. The method lacks data regarding the possible personalization of ISAH therapy in people of an early period of old age and senile age as a clinical problem based on the identification of a specific diagnostic complex of biomarkers in the blood and analysis of their interaction, which contributes to the inclusion of effective and safe antihypertensive drugs with appropriate by the mechanism of action.

Known patent for the invention of the Russian Federation No. 2525156 "Method for the treatment and prevention of arterial hypertension and a pharmaceutical composition for the treatment of arterial hypertension", IPC A61K 39/395, A61P 9/12, publ. 08/10/2014, which presents a method for the treatment and prevention of hypertension by introducing a drug into the body based on an activated potentiated form of ultra-low doses of affinity purified antibodies to the angiotensin II receptor (activated potentiated form of antibodies to the C-terminal fragment of the AT1 receptor for angiotensin II), prepared by repeated serial dilution and external exposure according to the invention, an activated potentiated form of ultralow doses of affinity-purified antibodies to endothelial NO synthase (activated potentiated form of antibodies to endothelial NO synthase) is additionally simultaneously and simultaneously administered. The method involves the use of a single drug - one dosage form with a mixture of different homeopathic dilutions of antibodies to the C-terminal fragment of the AT1 receptor of angiotensin II in combination with a mixture of different homeopathic dilutions of antibodies to endothelial NO synthase. An activated potentiated form of antibodies to the C-terminal fragment of the AT1 receptor of angiotensin II and an activated potentiated form of antibodies to endothelial NO synthase are used in the form of an activated potentiated aqueous or aqueous-alcoholic solution of each component obtained during repeated serial dilution in an aqueous or aqueous-alcoholic solvent and intermediate external mechanical impact - vertical shaking. A pharmaceutical composition is used based on an activated potentiated form of affinity-purified antibodies to the C-terminal fragment of the AT1 receptor of angiotensin II and to endothelial NO synthase in combination with known standard drugs used to treat diseases of the cardiovascular system of the following groups: ACE inhibitors, in including combined, beta-blockers, cardiac glycosides, calcium antagonists, lipid-lowering drugs, antiplatelet agents, antihypoxants, anticoagulants. A pharmaceutical composition is used in solid dosage form, which contains an effective amount of a neutral carrier granule and an pharmaceutically acceptable additive that is saturated with an activated potentiated form of antibodies to the angiotensin II receptor and an activated potentiated form of antibodies to endothelial NO synthase of a neutral carrier. The claimed method of taking the pharmaceutical composition is 1-2 tablets 2-4 times a day.

However, the known method does not imply an assessment of the effectiveness and safety of the proposed composition containing activated potentiated forms of ultra-low doses of antibodies to the C-terminal fragment of AT1 angiotensin II receptor and to endothelial NO synthase in human clinical trials; the method does not involve identifying a correspondence between the detection of a diagnostic complex of ISAG biomarkers in the blood and its progression in patients of an early period of old age and senile age; there is no analysis of the dynamics of the proteomic blood profile of the biomodels of AG-laboratory animals before and against the background of the administration of the claimed pharmaceutical composition containing activated potentiated forms of ultra-low doses of antibodies to the C-terminal fragment of angiotensin II receptor AT1 and to endothelial NO synthase to detail the mechanism the effects and predicted efficacy and safety of the new pharmaceutical composition in humans.

Known RF patent No. 2648453 "Method for the early diagnosis of various forms of essential arterial hypertension in children and adolescents", IPC G01N 33/48, publ. 03/26/2018, which presents an early diagnosis of various forms of essential hypertension in children and adolescents, for which the concentration of nitric oxide in the serum, endothelin-1 in plasma and serotonin in plasma and platelets is determined, the obtained data are compared with the upper values of such indicators in healthy children and based on the obtained ratios diagnose labile or stable form of hypertension. The method provides reliable diagnosis of hypertension in children and adolescents at an early stage of the disease and the possibility of its timely correction: an increase in the concentration of nitric oxide (NO) in serum with labile hypertension and a decrease in stable hypertension, an increase in the concentration of endothelin-1 (ET-1) and serotonin (5-HT) in plasma and serum; and serotonin (5-HT) in blood platelets in adolescents with various forms of essential hypertension compared with the norm.

However, the known method relates to the early diagnosis of a labile or stable form of hypertension only in children and adolescents and does not include the diagnosis of hypertension in other age groups, including ISAG in groups of patients of an early period of old age and senile age; the method does not imply a preliminary comprehensive assessment of the molecular (proteomngo) profile of blood plasma and platelets based on high-tech proteomics methods (MALDI-TOF mass spectrometry), followed by a quantitative assessment of the most frequently registered markers using enzyme-linked immunosorbent assay (ELISA).

Known patent for the invention of the Russian Federation No. 2445913 "A method for predicting the occurrence of arterial hypertension in patients with coronary heart disease", IPC AB 5/00, publ. 03/27/2012, which presents a method for predicting hypertension in patients with coronary heart disease with isolated stable angina pectoris, without clinical data for hypertension and cases of high blood pressure recorded by a doctor, and other direct indications of its existence in a patient based on the determination of anamnestic factors risk, anthropometric and morpho-functional indicators according to echocardiographic and coronary angiographic studies and calculation of prognostic indicator (PP) according to the formula developed by the author. With a value of PP> 1, they judge the possibility of the development of hypertension, and with a value of PP ≤1 - the absence of such a forecast.

However, the known method does not present the molecular phenotypes of blood of each variant of hypertension, which determine the modifiable parameters proposed in the author's formula; the method does not imply a prognostic correlation between the detection of a certain complex of biomarkers in the blood, on the one hand, and anamnestic risk factors, anthropometric and morphofunctional indicators according to echocardiographic and coronary angiographic studies in ISAH in groups of patients of early and old age.

Among foreign patents, the patent of Ukraine No. 66731 was discovered "Method for predicting the achievement of target blood pressure in patients with arterial hypertension", IPC A61K 31/00, publ. 01/10/2012, which presents a method for predicting the achievement of target blood pressure in patients with ISAH based on monitoring blood pressure taking into account the outcome of the previous treatment (lack of use of two or more antihypertensive drugs, ACE inhibitors, high risk of cardiovascular disease complications). The detection of at least one of these parameters indicates a decrease in the probability of achieving the target blood pressure by 38%, if at least two factors are detected, the probability of achieving the target blood pressure is reduced by 34%, three factors - by 65%, four factors - by 66 %

However, the known method does not involve the analysis of molecular profiles of the patient’s blood plasma, does not take into account the characteristics of age; the method does not involve revealing a prognostic correlation between the diagnostic complex of biomarkers in the blood, on the one hand, and standard methods of clinical and instrumental studies and laboratory tests for ISAH in groups of patients of an early period of old age and senile age.

Known application of the Russian Federation for invention No. 2003133640 "Method for predicting a variant of arterial hypertension in elderly and senile patients" dated 04/20/2005, which presents a method for predicting a variant of arterial hypertension in elderly and senile patients by determining the vasomotor function of the endothelium, in which patients risk groups additionally determine the level of endothelin 1, endothelium-dependent vasodilation, endothelium independent dilation, when certain values are established which predict the development of systolic-diastolic hypertension or isag.

However, the known method does not involve a comprehensive analysis of the molecular profile of blood plasma, includes the determination of a single indicator-level of endothelin 1; the method does not provide for the identification of prognostic correspondence between the diagnostic complex of biomarkers in the blood, on the one hand, and indicators of standard methods of clinical and instrumental studies and laboratory tests for ISAH in groups of patients of an early period of old age and senile age.

One of the closest analogues can be considered the "Method of individual choice of antihypertensive drug for the treatment of arterial hypertension", application for invention of the Russian Federation No. 99126345, IPC AB 5/02, A61P 9/12, publ. dated October 27, 2001, in which medical treatment is carried out with preliminary laboratory and instrumental examinations and a test survey. In this case, the patient is individually selected a drug based on the generated data on his condition (including parameters characterizing the main diagnosis and concomitant diseases); using the Bayes formula, according to which the drug that received the highest assessment of posterior probability is considered the best for antihypertensive therapy for a particular patient. The method differs in that it analyzes available clinical and laboratory diagnostic diagnostic signs from the selected 23 most informative: OPSS, heart rate, stroke volume (UO), left ventricular hypertrophy (LVH), cholesterol, creatinine, glucose, uric acid, potassium blood , orthostatic reactions, age, pregnancy, bradycardia, heart block, arrhythmias, angina pectoris, gout, diabetes mellitus, chronic obstructive pulmonary disease (COPD), cardiac and renal failure, peripheral artery disease and encephalopathy. The method is characterized in that the determination of the most preferred drug, of the 26 proposed antihypertensive drugs of 8 known pharmacological groups, is based on the maximum correspondence of the effects of the drug on the state parameters of the patient with AH in need of correction, the most preferred drug in the particular case of the disease is selected by calculating for each drug a posterior probability of its choice according to the Bayes formula.

However, the method does not provide an analysis of the molecular blood profiles of each variant of AH, which determine the modifiable parameters proposed for the choice of a medicinal product according to the Bayes formula; the method does not involve the identification of a prognostic correspondence between the detection of a specific complex of biomarkers in blood plasma and the parameters included in the method that determine the course of arterial hypertension in a patient, including ISAG in groups of patients of an early period of old age and senile age, and the choice on the basis of this correspondence of a hypotensive drug with a targeted mechanism of action.

The objective of the invention is the early diagnosis and increase the effectiveness of the treatment of isolated systolic hypertension of the 1st degree in patients in the early period of old age and senile age.

The technical result of the invention is to reduce the dose of antihypertensive drugs, increase the efficiency, safety of the treatment while reducing the economic costs of pharmacotherapy.

The objective is achieved by performing molecular diagnostics of the blood plasma of patients with ISAG grade 1 of an early period of age (65-74 years) and in the case of detecting the presence of expression of cathepsin G equal to 3.5 ng / ml or more, myeloperoxidase equal to 23 Units / ml or more, hypoxia of inducible factor Ia equal to 280 pg / ml or more, hyaluronidase equal to 9 IU / l or more, kininogen-1 equal to 85 ng / ml or more, pyruvate kinase equal to 10 IU / ml or more, and alpha subunit ATP synthases of 60 pg / ml or more carry out personalized therapy by administering a combination of an angiotensin II receptor blocker and a slow calcium channel blocker. In patients with ISAG of senile age (over 75 years), in addition to the obtained molecular profile, the quantitative presence of protein expression is determined in blood plasma. If apolipoprotein D, equal to or more than 30 ng / ml, a transforming growth factor beta-1, equal to 900 pg / ml or more, fibulin-5, equal to 250 pg / ml or more, is detected, personalized therapy is also carried out by prescribing a combination angiotensin II receptor blocker; and slow calcium channel blocker.

Search for molecular diagnostic profiles of blood plasma with ISAG grade 1 in patients of an early period of old age (65-74 years) and senile age (over 75 years) based on proteomic research methods, including high-quality proteomic phenotyping of blood plasma using SDS-PAGE-MALDI- TOF-TOF mass spectrometry with an assessment of the expression intensity of each peptide fragment and protein after extraction and a quantitative assessment of the level of protein in the blood in the case of its high expression in the blood plasma of a patient using enzyme-linked immunosorbent assay (ELISA), the interaction of proteins detected in high expression blood plasma with risk factors and indicators of standard methods for the study of the cardiovascular system with ISAG grade 1 in groups of people of an early period of old age (65-74 years) and senile age (over 75 years), personalize the selection and use of antihypertensive drugs of priority groups with considering the mechanism of action of the drug in The identified molecular profile of the patient's blood plasma.

The method is as follows.

3 months after the diagnosis of ISAG grade 1 based on indicators of standard methods for examining the cardiovascular system in hypertension (physical examination; ECG; SMAD; doppler echocardiography; ultrasonography of the brain vessels; metabolic profile of blood and urine - glycemia, creatinine, lipid profile, micro and macroalbuminuria, proteinuria) and taking one of the regimen of standard ISAH therapy with antihypertensive drugs from the priority list (2018 European Society of Cardiology (ЕОК) / European Society for Arterial Hypertension (ЕОАГ) Recommendations for the treatment of patients with arterial hypertension // Russian Journal of Cardiology 2018; 23 ( 12), pp. 143-228) - a slow calcium channel blocker (BMCC) amlodipine, in a daily dose of 5 mg or / and diuretic indapamide retard, in a daily dose of 1.5 mg; either a valsartan receptor blocker for angiotensin II (ARB II), in a daily dose of 80 mg or / and an indapamide retard diuretic, in a daily dose of 1.5 mg, evaluate the effectiveness of therapy using a molecular diagnostic blood profile based on qualitative and quantitative blood phenotyping using SDS-PAGE-MALDI-TOF-TOF-mass spectrometry / ELISA and personalization of the choice, mode and duration of taking antihypertensive drugs for combination therapy from the priority list depending on the detected proteomic profile of blood plasma. When standard therapy is detected after 3 months in the proteomic profile of blood plasma in a patient with ISAH grade 1 of an early period of old age, qualitative and quantitative expression of cathepsin G, myeloperoxidase, hypoxia of inducible factor Ia, hyaluronidase, kininogen-1, pyruvate kinase, subunit alpha ATP synthase with with a high quantitative level of each biomarker in the blood and in a patient with ISAH grade 1 senile age, in addition to the above proteins of qualitative and quantitative expression of apolipoprotein D, transforming growth factor beta-1, fibulin-5 with a confirmed high quantitative level of each biomarker in the blood, the patient is transferred from ISAG 1 degree with BMKK amlodipine, in a daily dose of 5 mg or / and diuretic indapamide retard, in a daily dose of 1.5 mg, or BRII valsartan, in a daily dose of 80 mg or / and diuretic indapamide retard, in a daily dose of 1 , 5 mg, taken with BPAII, valsartan, in a starting daily dose of 80 mg or / and BMKK amlodipine , in a daily dose of 5 mg when detecting a high level of protein / protein markers in the blood plasma in the identified proteomic blood profile of the patient.

The method was developed according to the results of the examination of 146 ISAH patients of the 1st degree without any other significant concomitant pathology: patients in the early period of old age (93 people), elderly patients (53 people), among them 86 women and 60 men (average age patients in the early period of old age 69.4 ± 0.2 years, in old age - 79.7 ± 0.2 years). According to the daily monitoring of blood pressure (BPM), 93 patients of an early period of old age had the following systolic and diastolic blood pressure values: SBP = 152.8 ± 3.6 mm Hg. st .; DBP = 77.8 ± 1.5 mm Hg. Art. According to the Smad, 53 senile patients had the following systolic and diastolic blood pressure values: GARDEN = 159.1 ± 1.2 mm Hg. st .; DBP = 77.2 ± 1.5 mm Hg. Art. Among patients, the proportion of patients with a SCORE> 5% risk was 100%. The proportion of patients with ECG data: Sokolov-Lyon index (SV1 + RV5-6)> 38 mm in the early period of old age - 75.2%, in old age - 81.8%.

The comparison group consisted of 60 examined without ISAG, without significant concomitant pathology, including those examined without ISAG in the early period of old age (30 people), in old age (30 people), among them 24 men and 36 women, comparable by age with the study group: p> 0.05 (the average age of the examined from the comparison group-1 is 69.4 ± 0.2 years in the early period of old age and 77.9 ± 0.2 years, respectively).

In all groups, the presence of high-quality expression of proteins in the molecular profile of the blood plasma of patients with ISAH grade 1 and examined in the comparison group was assessed, followed by a quantitative assessment of the level of the most frequently detected plasma proteins.

Clinical examples.

Example 1

Patient N., 68 years old, was admitted to the clinic of internal diseases of FSBEI HE “Rostov State Medical University” (Rostov-on-Don) with complaints of elevations of the GARDEN to 156 mm Hg. Art., DBP up to 74 mm Hg, heart rate up to 80 beats per minute, mainly from 15.00 to 20.00, fatigue, headaches in the occipital region, tinnitus, unsteadiness when walking, pain of a pressing nature in the region of the heart, palpitations periodically symmetrical edema in the ankle regions, impaired memory and attention. For the first time, complaints of unstable blood pressure appeared at 50 years old, a rapid deterioration noted in old age. From the moment of verification of the diagnosis of arterial hypertension, she took the following drugs in various combinations: enalapril (ACE inhibitor), hypothiazide, indapamide retard (diuretic), bisoprolol (beta-blocker), amlodipine (slow calcium channel blocker), atorvastatin, acetylsalicylic acid.

On examination: height 168 cm, weight 85 kg, BMI = 30.3, OT = 85 cm.

The skin is pale, dry. Slight swelling on the feet. Visual examination data: vesicular breathing in the lungs, no wheezing, cardiac sounds muffled, rhythmic, II accent above the aorta, there is no systolic murmur when auscultating the carotid arteries, the pulse on the peripheral arteries is preserved. Measurement of office blood pressure with an interval of 2 minutes, sitting in a quiet comfortable environment for 5 minutes before the start of blood pressure measurement: 1 measurement - blood pressure = 150/82 mm Hg. Art., heart rate-86 beats per minute, 2 measurement - HELL = 144/80 mm RT. Art., heart rate-88 beats per minute; 3 dimension - HELL = 146/80 mm RT. Art., heart rate-90 beats per minute; BH-16 per minute, the abdomen on palpation is painless and soft, the liver is enlarged by 0.25 cm. The lumbar region is not visually changed, the symptom of efflux is negative on both sides, there is no dysuria. The thyroid gland during palpation is not enlarged.

Risk factors: a family history of hypertension, coronary heart disease, stroke along the lines of the mother and father; the diet is dominated by a diet high in fat and carbohydrates, lack of physical activity, periodically notes sleep disturbance (intrasomnic disorders)

Cognitive functions are preserved (orientation in time, place and personality; speech and counting; ability to judge; logical thinking). Emotional status and mood are not broken. Muscle tone and strength saved. There is a slight loss of muscle mass. Static balance and coordination within normal limits. Violations of sensitivity, reflexes, the presence of pathological reflexes were not detected. The function of the autonomic nervous system is not impaired.

Diagnosis: High-risk arterial hypertension 1 degree.

Indicators of instrumental studies (before personalization of therapy).

Data of repeated office measurements of blood pressure and heart rate (6 repeated visits): GARDEN maximum - 155 mm RT. st .; GARDEN minimum - 140 mm RT. st .; DBP maximum - 85 mm RT. st .; DBP minimum - 80 mm RT. st .; The maximum heart rate is 90 beats per minute; Heart rate minimum-80 beats per minute; average GARDEN - 147 mm RT. st .; average DBP - 82 mm RT. Art., heart rate average-85 beats per minute.

Repeated off-site measurements of blood pressure and heart rate (6 days, 2 times a day): GARDEN maximum - 155 mm RT. st .; GARDEN minimum - 140 mm RT. st .; DBP maximum - 85 mm RT. st .; DBP minimum - 70 mm RT. st .; average GARDEN - 147 mm RT. st .; average DBP - 77 mm RT. st .; The maximum heart rate is 84 beats per minute; Heart rate minimum-70 beats per minute; The average heart rate is 77 beats per minute.

ECG in 12 leads: Sokolov-Lyon index (SV1 + RV5> 35 mm). Left ventricular hypertrophy.

Echocardiography: CSLH - 34 mm; KDDLZH - 47 mm; KSOLZH - 48 ml; CEDAW - 105 ml; MZhPS - 1.5 mm; MZhPd - 1,0 mm; TZsts - 1.6 mm; TZStd -1.1 mm; LP - 40 mm; MLJ - 180 g; Heart rate - 80 beats / min; UO - 72 ml; MO - 5 l / min; UI - 36 ml / m ² ; PV - 65%; E - 72 cm / sec; A - 64 cm / sec; E / A -1.1; IVRT - 82 ms; DT - 238 ms; Rs - 47 mm; Ls - 52 mm; Rd - 54 mm; Ld - 71 mm; Lc - 67 mm; Ld - 85 mm.

Ultrasound examination of the carotid arteries: systolic LSC according to OSA-79 cm / sec; systolic BFV by ICA-72 cm / sec; systolic LSK according to NSA-75 cm / sec; systolic BFV by PA (V1) -63 cm / sec; PI OCA-1.4 srvc units; RI OCA-0.75 srvc units

Ankle-brachial index (LPI) -0.85, carotid-femoral SPV -11 cm / s

Fundoscopy: microaneurysms, small intraretinal hemorrhages, retinal edema.

The conclusion of the ophthalmologist. Hypertensive retinopathy 2 degrees.

Indicators of routine laboratory tests (before personalization of therapy).

Hemoglobin - 132 g / l; fasting blood glucose - 5.8 mmol / l; HbAc1 - 5.5%, total cholesterol - 7.2 mmol / L, LDL cholesterol - 4.5 mmol / L; HDL cholesterol - 0.7 mmol / l; TG - 1.8 mmol / l; creatinine - 68 μmol / l, GFR - 95 ml / min × 1.73 m ² ; uric acid - 340 μmol / l; ALT - 32ME, ACT - 26 ME, GGTP - 28 U / L; total bilirubin - 10.5 μmol / l, direct bilirubin-2.5 μmol / l; serum potassium - 4.1 mmol / l, serum sodium - 141 mmol / l. Clinical analysis of urine: protein - not detected; sediment microscopy - leukocytes 3-4 in the field of view, squamous epithelium-0-1 in the field of view, red blood cells - 0-1 in the field of view; urine albumin / creatinine - 1.6 mg / mmol creatinine.

MRI: periventricular and subcortical ischemic lesions, diffuse leukoaraiosis with expansion of the ventricles and subarachnoid spaces are determined.

The conclusion of the neurologist. Hypertensive encephalopathy of 1 degree.

Quantitative ELISA data of peptide and protein markers in blood plasma, high-quality expression of which was revealed after 3 months of standard therapy by SDS-PAGE-MALDI-TOF mass spectrometry of the patient's blood plasma: cathepsin G - 3.8 ng / ml, myeloperoxidase - 24, 7 U / ml, hypoxia inducible factor Ia - 298 pg / ml, hyaluronidase activity - 10.2 mU / l, kininogen-1 - 91.5 ng / ml, pyruvate kinase - 10.5 U / ml, alpha ATP synthase subunits - 68 pg / ml

Conducted antihypertensive therapy (before personalization). BMKK amlodipine, in a daily dose of 5 mg + diuretic indapamide retard, in a daily dose of 1.5 mg.

Conducted antihypertensive therapy (personalization of therapy). The combined intake of ARB II valsartan in a daily dose of 80 mg + BMKK amlodipine in a daily dose of 5 mg.

The survey was conducted according to the above scheme.

The effectiveness of personalized treatment was noted 3 months after taking the new ISAH treatment regimen and was expressed as follows. There was a decrease in the subjective symptoms of ISAH: a decrease in fatigue, frequency and intensity of headaches in the occipital region, tinnitus, unsteadiness when walking, pressing pains in the heart region, palpitations, lack of symmetrical edema in the ankles, memory and concentration.

Positive changes in the indices of central and cerebral hemodynamics were noted: measurements of office blood pressure with an interval of 2 minutes, sitting in a calm comfortable environment for 5 minutes before the start of blood pressure measurement - 1 measurement - blood pressure = 130/70 mm Hg. Art., heart rate-84 beats per minute, 2 dimension - HELL = 125/70 mm RT. Art., heart rate-86 beats per minute; 3 dimension - HELL = 120/70 mm RT. Art., heart rate-86 beats per minute; data of repeated off-site measurements of blood pressure and heart rate (6 days, 2 times a day): GARDEN maximum - 135 mm RT. st .; GARDEN minimum - 120 mm RT. st .; DBP maximum - 70 mm RT. st .; DBP minimum - 65 mm RT. st .; average GARDEN - 127 mm RT. st .; average DBP - 67 mm RT. st .; The maximum heart rate is 84 beats per minute; Minimum heart rate is 66 beats per minute; Heart rate average-80 beats per minute; data of an ultrasound examination of the carotid arteries: systolic LSC by OSA - 87 cm / sec; systolic BFV by ICA - 76 cm / sec; systolic LSK according to NSA - 77 cm / sec; systolic BFV by PA (V1) - 66 cm / sec; PI for OCA - 1.6 srvc units; RI for OCA - 0.7 srvc units; carotid-femoral SPV - 10 cm / s.

The positive dynamics of the indicators of echocardiography was noted: KSDLZH - 31 mm; KDDLZH - 43 mm; KSOLZH - 42 ml; CEDAW - 101 ml; MZhPS - 1.4 mm; MFD - 0.9 mm; TZsts - 1.4 mm; TZStd - 0.9 mm; PL - 37 mm; MMLF - 172 g; Heart rate - 76 beats / min; UO - 71 ml; MO - 5 l / min; UI - 35 ml / m2; PV - 65%; E - 73 cm / sec; A - 62 cm / sec; E / A - 1.2; IVRT - 80 ms; DT - 229 ms; Rs - 45 mm; Ls - 47 mm; Rd - 52 mm; Ld - 70 mm; Lc - 65 mm; Ld - 78 mm.

Found positive dynamics of the results of fundoscopy: a decrease in the number of small intraretinal hemorrhages, retinal edema.

The positive dynamics of the following laboratory tests is shown: total cholesterol - 5.5 mmol / l, LDL cholesterol - 3.5 mmol / l; HDL cholesterol - 0.9 mmol / l; TG - 1.2 mmol / l; GFR - 102 ml / min × 1.73 m ² ; urine albumin / creatinine - 1.2 mg / mmol creatinine.

Significant changes in the data of quantitative ELISA of peptide and protein markers of blood plasma were detected: cathepsin G - 3.5 ng / ml, myeloperoxidase - 23 U / ml, hypoxia-induced factor Ia - 282 pg / ml, hyaluronidase activity - 9.6 mU / l, kininogen-1 - 85 ng / ml, pyruvate kinase - 10 U / ml, subunits of alpha ATP synthase - 64 pg / ml

The patient was discharged from the department with a diagnosis of Arterial hypertension of 1 degree, 2 stages, high risk. Hypertensive retinopathy 2 degrees. Hypertensive encephalopathy, 1 degree.

The patient is recommended: 1) measures to change the coolant, which significantly reduce blood pressure, include limiting the use of salt and alcohol, high consumption of vegetables and fruits, reducing body weight and maintaining ideal weight, regular physical activity; 2) daily monitoring of blood pressure and pulse; 3) antihypertensive therapy is carried out in accordance with the correction - valsartan - 80 mg at 8.00 and amlodipine - 5 mg / day at 21:00; 5) pitavastatin - 2 mg at 19:00 after eating; acetylsalicylic acid - 100 mg per day at 19:00 after eating; 6) observation by the general practitioner and cardiologist of the polyclinic and evaluation of the effectiveness of antihypertensive therapy at the polyclinic stage of treatment according to the developed scheme after 3 and 6 months.

In the process of monitoring patient complaints, indicators of physical examination, parameters of office and off-site blood pressure and pulse, cerebral blood flow, clinical analysis of urine with an assessment of albumin / creatinine in the urine, Reberg test, parameters of the blood biochemical profile, re-examination of the ophthalmologist and neurologist of the patient after personalizing the regimen therapy using a combination of a blocker to the angiotensin II receptor valsartan and a slow calcium channel blocker amlodipine, stabilization of all indicators was noted at the level achieved at the initial stage of personalized treatment (first 3 months of therapy).

Example 2

Patient S., 77 years old, was admitted to the clinic of internal diseases of FSBEI HPE “Rostov State Medical University” (Rostov-on-Don) with complaints of elevations of the GARDEN to 150 mm Hg. Art., DBP up to 80 mm Hg, heart rate up to 95 beats per minute, mainly from 14.00 to 18.00, fatigue, headaches in the parietal and occipital region, ringing and tinnitus, dizziness when moving from a horizontal position to vertical, pain of a pressing nature in the region of the heart, palpitations, symmetrical swelling in the ankles, impaired memory and concentration. For the first time complaints of unstable blood pressure appeared at age 60, a rapid deterioration noted in old age. From the moment of verification of the diagnosis of arterial hypertension, he took the following drugs in various combinations: perindopril (ACE inhibitor), hypothiazide, indapamide retard (diuretics), bisoprolol (beta-blocker), amlodipine (slow calcium channel blocker), rosuvastatin, acetylsalicylic acid.

On examination: height 172 cm, weight 92 kg, BMI = 31.5, OT = 92 cm.

The skin is pale, dry. Small swelling on the feet and in the ankles is symmetrical. Visual examination data: vesicular breathing in the lungs, no wheezing, cardiac sounds muffled, rhythmic, II accent above the aorta, there is no systolic murmur when auscultating the carotid arteries, the pulse on the peripheral arteries is preserved. Measurement of office blood pressure with an interval of 2 minutes, sitting in a calm comfortable environment for 5 minutes before the start of blood pressure measurement: 1 measurement - blood pressure = 155/80 mm Hg. Art., heart rate-90 beats per minute, 2 measurement - BP = 150/80 mm RT. Art., heart rate-88 beats per minute; 3 dimension - HELL = 145/78 mm RT. Art., heart rate-88 beats per minute; BH-17 per minute, the abdomen on palpation is painless and soft, the liver is enlarged by 0.5 cm. The lumbar region is not visually changed, the symptom of effusion is negative on both sides, dysuria. The thyroid gland during palpation is not enlarged.

Risk factors: a family history of hypertension, coronary heart disease in the mother and father; a diet high in fat predominates in the diet, lack of physical activity, periodically notes sleep disturbance (presomnic disorders)

Cognitive functions are preserved (orientation in time, place and personality; speech and counting; ability to judge; logical thinking). Emotional status and mood are not broken. Muscle tone and strength saved. There is a slight loss of muscle mass. Static balance and coordination within normal limits. Violations of sensitivity, reflexes, the presence of pathological reflexes were not detected. The function of the autonomic nervous system is not impaired.

Diagnosis: High-risk arterial hypertension 1 degree.

Indicators of instrumental studies (before personalization of therapy).

Data of repeated office measurements of blood pressure and heart rate (6 repeated visits): GARDEN maximum - 155 mm RT. st .; GARDEN minimum - 140 mm RT. st .; DBP maximum - 80 mm RT. st .; DBP minimum - 68 mm RT. st .; The maximum heart rate is 90 beats per minute; Minimum heart rate is 88 beats per minute; average GARDEN - 147 mm RT. st .; average DBP - 74 mm RT. Art., heart rate average-89 beats per minute.

Repeated off-site measurements of blood pressure and heart rate (6 days, 2 times a day): GARDEN maximum - 145 mm RT. st .; GARDEN minimum - 135 mm RT. st .; DBP maximum - 80 mm RT. st .; DBP minimum - 65 mm RT. st .; average GARDEN - 140 mm RT. st .; average DBP - 72 mm RT. st .; The maximum heart rate is 90 beats per minute; Minimum heart rate is 72 beats per minute; The average heart rate is 81 beats per minute.

ECG in 12 leads: Sokolov-Lyon index (SV1 + RV5> 35 mm). Left ventricular hypertrophy. Violation of the processes of repolarization in the myocardium.

Echocardiography: CSLH - 35 mm; KDDLZH - 47 mm; KSOLZH - 48 ml; CEDAW - 109 ml; MZhPS - 1.6 mm; MFD - 1.1 mm; TZsts - 1.7 mm; TZStd -1.2 mm; LP - 41 mm; MMWF - 182 g; Heart rate - 81 beats / min; UO - 73 ml; MO - 5.3 l / min; UI - 37 ml / m ² ; PV - 66%; E - 72 cm / sec; A - 65 cm / sec; E / A -1.1; IVRT - 84 ms; DT - 240 ms; Rs - 49 mm; Ls - 55 mm; Rd - 56 mm; Ld - 74 mm; Lc - 68 mm; Ld - 85 mm.

Ultrasound examination of the carotid arteries: systolic LSC according to OSA-77 cm / sec; systolic BFV by ICA-69 cm / sec; systolic LSK according to NSA-74 cm / sec; systolic BFV by PA (V1) -62 cm / sec; PI OCA-1.4 srvc units; RI OCA-0.75 srvc units

Ankle-brachial index (LPI) -0.80, carotid-femoral SPV -12 cm / s

Fundoscopy: narrow constrictions, microaneurysms, small intraretinal hemorrhages, retinal edema.

The conclusion of the ophthalmologist. Hypertensive retinopathy 2 degrees.

Indicators of routine laboratory tests (before personalization of therapy).

Hemoglobin - 142 g / l; fasting blood glucose -5.6 mmol / l; HbAc1 -5.7%, total cholesterol - 7.1 mmol / L, LDL cholesterol - 4.3 mmol / L; HDL cholesterol - 0.8 mmol / l; TG - 1.9 mmol / l; creatinine - 85 μmol / l, GFR - 92 ml / min × 1.73 m ² ; uric acid - 346 μmol / l; ALT - 37ME, ACT - 28 ME, GGTP - 26 U / L; total bilirubin - 11.2 μmol / l, direct bilirubin - 2.7 μmol / l; serum potassium - 3.9 mmol / l, serum sodium -135 mmol / l. Clinical analysis of urine: protein - not detected; microscopy of sediment - 3-4 leukocytes in the field of view, squamous epithelium-1-2 in the field of view, red blood cells - 1-2 in the field of view; urine albumin / creatinine - 1.8 mg / mmol creatinine.

MRI: subcortical ischemic lesions, diffuse leukoaraiosis with expansion of the ventricles and subarachnoid spaces are determined.

The conclusion of the neurologist. Hypertensive encephalopathy, 1 degree.

Quantitative ELISA data of peptide and protein markers in blood plasma, high-quality expression of which was detected after 3 months of standard therapy by SDS-PAGE-MALDI-TOF mass spectrometry of the patient's blood plasma: cathepsin G - 4.0 ng / ml, myeloperoxidase - 27 units / ml, apolipoprotein D - 34 ng / ml, hypoxia inducible factor Ia - 373 pg / ml, transforming growth factor beta-1-918 pg / ml, hyaluronidase activity - 12 mU / l, kininogen-1 - 108 ng / ml, fibulin-5 - 284 pg / ml, pyruvate kinase - 12 U / ml, subunits of alpha ATP synthase - 77 pg / ml.

Conducted antihypertensive therapy (before personalization). ARB II valsartan, in a daily dose of 80 mg + diuretic indapamide retard, in a daily dose of 1.5 mg.

Conducted antihypertensive therapy (personalization of therapy). The combined intake of ARB II valsartan in a daily dose of 80 mg + BMKK amlodipine in a daily dose of 5 mg.

The survey was conducted according to the above scheme.

The effectiveness of the treatment was observed 3 months after taking the new ISAH treatment regimen and was expressed as follows. There was a decrease in the subjective symptoms of ISAH: a decrease in fatigue, frequency and intensity of headaches in the parietal and occipital region, tinnitus and noise in the ears, shakiness when walking, pains of a pressing nature in the region of the heart, palpitations in orthostasis, the absence of symmetrical edema in the feet and ankles , improving memory and concentration.

Positive changes in the indices of central and cerebral hemodynamics were noted: measurements of office blood pressure with an interval of 2 minutes, sitting in a calm comfortable environment for 5 minutes before the start of blood pressure measurement - 1 measurement - blood pressure = 140/80 mm Hg. Art., heart rate-82 beats per minute, 2 dimension - HELL = 135/75 mm Hg. Art., heart rate-80 beats per minute; 3 dimension - HELL = 130/70 mm RT. Art., heart rate-76 beats per minute; data of repeated off-site measurements of blood pressure and heart rate (6 days, 2 times a day): GARDEN maximum - 145 mm RT. st .; GARDEN minimum - 120 mm RT. st .; DBP maximum - 80 mm RT. st .; DBP minimum - 60 mm RT. st .; average GARDEN - 132 mm RT. st .; average DBP - 70 mm RT. st .; The maximum heart rate is 82 beats per minute; Minimum heart rate is 66 beats per minute; Heart rate average-74 beats per minute; data of an ultrasound examination of the carotid arteries: systolic LSC by OSA - 79 cm / sec; systolic BFV by ICA - 69 cm / sec; systolic LSK according to NSA - 75 cm / sec; systolic BFV according to PA (V1) - 64 cm / sec; PI for OCA - 1.6 srvc units; RI for OCA - 0.72 srvc units; carotid-femoral SPV - 10 cm / s.

Echocardiography: XDLC -33 mm; KDDLZH - 46 mm; KSOLZH - 45 ml; CEDAW - 104 ml; MZhPS - 1.5 mm; MFD - 0.9 mm; TZsts - 1.5 mm; TZStd -1.0 mm; PL - 39 mm; MMWF - 178 g; Heart rate - 78 beats / min; UO - 72 ml; MO - 5.2 l / min; UI - 36 ml / m2; PV - 67%; E - 73 cm / sec; A - 63 cm / sec; E / A -1.1; IVRT - 83 ms; DT - 230 ms; Rs - 46 mm; Ls - 49 mm; Rd - 53 mm; Ld - 73 mm; Lc - 66 mm; Ld - 81 mm.

A positive dynamics of the results of fundoscopy was found: a decrease in the number of narrow constrictions and small intraretinal hemorrhages, retinal edema, and soft exudative foci.

The positive dynamics of the following laboratory tests is shown: total cholesterol - 6.0 mmol / l, LDL cholesterol - 3.7 mmol / l; HDL cholesterol -0.9 mmol / l; TG - 1.5 mmol / l; GFR - 100 ml / min × 1.73 m ² ; urine albumin / creatinine - 1.3 mg / mmol creatinine.

Significant changes in the data of quantitative ELISA of peptide and protein markers of blood plasma revealed by SDS-PAGE-MALDI-TOF mass spectrometry of the patient's blood plasma were revealed: cathepsin G - 3.7 ng / ml, myeloperoxidase - 26 U / ml, apolipoprotein D - 31 ng / ml, hypoxia inducible factor Ia - 365 pg / ml, transforming growth factor beta-1 - 906 pg / ml, hyaluronidase activity - 11 mU / l, kininogen-1 - 100 ng / ml, fibulin-5 - 276 pg / ml, pyruvate kinase - 11 U / ml, subunits of alpha ATP synthase - 68 pg / ml.

The patient was discharged from the department with a diagnosis of Arterial hypertension of 1 degree, 1 stage of high risk. Hypertensive retinopathy of 1 degree. Hypertensive encephalopathy, 1 degree.

The patient was recommended: 1) measures to change the coolant, which significantly reduce blood pressure, include limiting the use of salt and alcohol, high consumption of vegetables and fruits, reducing body weight and maintaining ideal weight, regular physical activity; 2) daily monitoring of blood pressure and pulse; 3) antihypertensive therapy is carried out in accordance with the correction valsartan-80 mg at 8.00 and amlodipine-5 mg / day at 21:00; 5) pitavastatin - 2 mg at 19:00 after eating; acetylsalicylic acid-100 mg per day at 19:00 after eating; 6) observation by the general practitioner and cardiologist of the polyclinic, evaluation of the effectiveness of antihypertensive therapy at the polyclinic stage of treatment according to the developed scheme after 3 and 6 months.

In the process of monitoring patient complaints, indicators of a physical examination, parameters of office and off-site blood pressure and pulse, cerebral blood flow, clinical analysis of urine with an assessment of urinary albumin / creatinine, Reberg test, parameters of the blood biochemical profile, re-examination of the ophthalmologist and neurologist of the patient after personalizing the regimen therapy using a combination of a blocker to the angiotensin II receptor valsartan and a slow calcium channel blocker amlodipine, stabilization of all indicators was noted at the level achieved at the initial stage of personalized treatment (first 3 months of therapy).

According to the prototype method, the treatment of hypertension is performed as follows: 1) data on the patient's condition are formed, including parameters of laboratory and instrumental examinations and a test survey that characterize the main diagnosis and concomitant diseases; 2) analyze available clinical and laboratory diagnostic diagnostic signs from the selected 23 most informative - OPSS, heart rate, UO, LVH, cholesterol, creatinine, glucose, uric acid, potassium blood, orthostatic reactions, age, pregnancy, bradycardia, blockade heart, arrhythmias, angina pectoris, gout, diabetes mellitus, chronic obstructive pulmonary disease (COPD), heart and kidney failure, peripheral artery disease and encephalopathy; 3) determine the most preferred drug from the 26 proposed antihypertensive drugs of 8 known pharmacological groups based on the maximum correspondence of the effects of the drug on the parameters of the patient's state of hypertension; 4) apply the Bayes formula, according to which the drug that received the highest assessment of posterior probability is considered the best for antihypertensive therapy for a particular patient.

The proposed method performs the diagnosis of ISAG 1 degree, personalized selection and use of antihypertensive drugs of priority groups based on the dominant clinical problem and predictive molecular (proteomic) profiling of blood plasma samples.

The proposed method for the diagnosis and personalized treatment of patients with ISAH of the 1st degree involves the individualized selection and use of antihypertensive drugs of priority groups, taking into account the molecular profile of blood plasma in each patient, and is aimed at increasing the effectiveness of treatment and, therefore, preventing the progression of ISAH by early drug exposure to expression intensity proteins present in the molecular profile of blood plasma and responsible for the development of ISAH grade 1 in patients in early adulthood and senile age. The method helps to reduce the dose of antihypertensive drugs, improves the efficiency, safety of the treatment while reducing the economic costs of pharmacotherapy.

Claims (1)

A method of treating isolated systolic arterial hypertension (ISAG) of the 1st degree in patients of an early period of old age - 65-74 years and senile age - over 75 years, characterized in that all patients with ISAG of the 1st degree of this age perform molecular diagnostics of blood plasma and determine the level expression of cathepsin G, myeloperoxidase, hypoxia of inducible factor Ia, hyaluronidase, kininogen-1, pyruvate kinase and alpha ATP synthase subunit, in elderly people, the expression level of apolipoprotein D, transforming growth factor beta-1, fibulin case-5, is additionally determined detecting the presence of cathepsin G expression level of 3.5 ng / ml or more, myeloperoxidase equal to 23 IU / ml or more, hypoxia of inducible factor Ia of 280 pg / ml or more, hyaluronidase equal to 9 IU / l or more, kininogen-1 of 85 ng / ml or more, pyruvate kinase of 10 U / ml or more, and alpha ATP synthase subunit of 60 pg / ml or more, apolipoprotein D, equal to or more than 30 ng / ml, transforming growth factor beta-1, equal to 900 pg / ml or more, fibulin-5, equal to 250 pg / ml or more, therapy is carried out by assigning a combination of a blocker to the angiotensin II receptor and a slow calcium channel blocker.