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38MEDICAL SCIENCES
ОЦ1НКА В1ДПОВ1Д1 НА Л1КУВАННЯ ТАУРИНОМ ТА МЕЛЬДОШСМ ЗА АМ1НОКИСЛОТАМИ КРОВ1 У ПОСТ1НФАРКТНИХ ХВОРИХ З ЦУКРОВИМ Д1АБЕТОМ 2 ТИПУ
Белжова Ю. О.
астрант, асистент кафедри внутршньо! медицини №4, Нацюнальний медичний ymiверситет iм. О. О. Богомольця
RESPONSE EVALUATION ON THE TAURIN AND MELDONIUM TREATMENT OF BLOOD AMINO ACIDS IN POST-INFARCTION PATIENTS WITH TYPE 2 DIABETES
Belikova J.
Postgraduate, Assistant at the Department of Internal Medicine No. 4,
Bogomolets National Medical University
Анотащя
Важливе значения у комбшованому ткувант хворих з постшфарктним кардюсклерозом (П1КС) з цу-кровим дiабетом типу 2 (ЦД 2) надаеться метаболiчнiй терапи (МТ), зокрема, препаратам з антиоксидант-ною активнютю, до яких належать таурин (ТН) та мельдонш (МН). Аналiз амшокислот кровi може бути важливим в контексл цiльового призначення метаболiчноl терапи та визначення необхiдностi змiни препарату при його неефективностг О^м впливу на фармакологiчний ефект метаболiчних препаратiв, доведено роль амшокислот у патогенезi iнсулiнорезистентностi, аритмiй, iшемiчних змiн мiокарда. Оцiнка за-лежносп вiдповiдi на лiкування ввд вихщного стану амiнокислотного спектра плазми кровi у хворих з П1КС та ЦД 2. Пащенти з П1КС та ЦД 2 (n=68) основно! групи отримували базову терапiю (БТ) П1КС та ЦД 2, та додатково МЕ по 1 капсулi 500 мг 2 рази на день i ТН по 1 капсулi 400 мг 3 рази на день протягом 3 тижшв. Пащенти групи порiвняння (п=30)приймали лише БТ. Пащенти основно! групи, тдгрупи тау-рину та мельдонiю, з позитивною вщповщдю на лiкування, отримали умовну назву "вiдповiдачiв". Хворi без динамiки або негативною вiдповiддю на лжування отримали умовну назву "невiдповiдачiв". Критерь ями вiдповiдi на лжування вважали данi холтерiвського монiторування ЕКГ: зниження на 50% загально! кшькосл шлуночкових екстрасистол, на 90% частоти парних шлуночкових екстрасистол, зникнення "про-б1жок" шлуночково! тахшарди, змешення шлькосп епiзодiв безбольово! гшеми мiокарда до 3 i менше протягом доби, сумарно! тривалостi гшеми протягом добу нижче 40 хвилин. Багатофакторний логiстичний регресiйний аналiз iз покроковим виведенням показникiв та проведенням ROC-аналiзу показав, що вихь дне вщношення таурин/аланiн виявилося амiнокислотним маркером, який проявив корелящю з результатами л^вання хворих пiдгруп таурину, мельдонш та мельдошю+ таурин незалежно вщ наявностi iнших чинник1в, за якими достовiрно вiдрiзнялися вiдповiдачi i невiдповiдачi ще! групи. У хворих, яш ввдповвда-ють значенню Таурин/Аланш(<0,043), та тирозин+феншалашн/метюнш у плазмi кровi >34,41,дощльним е призначення комплексу таурин+мельдонiй додатково до базово! терапи.
Abstract
Metabolic therapy (MT), in particular, antioxidant activity drugs, which include taurine (TN) and meldonium (MN) are of vital importance in the combined treatment of patients with postinfarction cardiosclerosis (PFCS) with type 2 diabetes (diabetes mellitus). Analysis of blood amino acids may be important in the context of the purpose of metabolic therapy and the need to change the drug in case of its ineffectiveness. In addition to influencing the pharmacological effect of metabolic drugs, the role of amino acids has been proved in the pathogenesis of insulin resistance, arrhythmias, and ischemic changes of the myocardium. The research objective was to evaluate the dependence of the response to treatment on baseline amino acid spectrum of blood plasma in patients with PFCS and type 2 diabetes mellitus. Patients with PICs and type 2 diabetes mellitus (n = 68) of the main group received basic therapy (BT) of PFCS and type 2 diabetes mellitus, and additionally 1 capsule 500mg 2 times a day of MN and 1 capsule 400mg 3 times a day for 3 weeks of TN. Patients in the comparison group (n = 30) took only BT. The main group and the taurine and meldonium subgroup patients having positive response to treatment were given the conditional name of "responders". Patients without dynamics or with a negative response to treatment were referred to as "non-responders". The criteria for responding to treatment were Holter monitor data: 50% reduction in total ventricular extrasystoles, 90% reduction in paired ventricular extrasystole frequency, disappearance of ventricular tachycardia jogging, reduction of episodes of painless myocardial ischemia to 3 and less times a day, and total duration of ischemia per day is less than 40 minutes. Multi factor logistic regression analysis with step-by-step indexing and ROC analysis showed that the initial taurine/alanine ratio was an amino acid marker, which showed correlation with the results of treatment of patients with taurine, meldonium and meldonium + taurine regardless of the presence of other factors that significantly differentiated the defendants and non-responders of this group. In patients with Taurine/Alanine (<0.043) and plasma tyrosine + phenylalanine/methionine>
34.41, it is appropriate to appoint the taurine + meldonium complex in addition to basic therapy.
Ключовi слова: цукровий дiабет 2-го типу, постшфарктний кардiосклероз, таурин, мельдонш. Keywords: 2nd type diabetes mellitus, postinfarction cardiosclerosis, taurine, meldonium.
Introduction
Metabolic therapy (MT), in particular, antioxidant drugs to which taurine (TN) and meldonium (MN) belong, is important in the combined treatment of post infarction patients with type 2 diabetes [4,7,8,14,16,17,19,24]. The effectiveness of MT depends not only on the presence of concomitant diseases in the patient, sex and age, but also from the individual condition of the so-called endogenous mechanisms of cardioprotection [9,10]. It has been proved that the amino acid spectrum is both a substrate and a regulator of enzyme activity [1,2,12]. Analysis of blood amino acids is important in the context of the purpose of metabolic therapy and the need to change the drug in case of its ineffectiveness [13,15,20,21]. Besides the influencing on the pharmacological effect of metabolic drugs, the role of amino acids has been proven in the pathogenesis of insulin resistance, arrhythmias, is-chemic myocardial changes [5,6,11,18,22].
Research objective: to evaluate the dependence of the response to treatment on the baseline of the amino acid spectrum of blood plasma in patients with PFCS and type 2 diabetes mellitus.
Amino acid composition of patients' blood was determined by the method of ion exchange liquid column chromatography on an automatic amino acid analyzer Microtechna T339.
Holter monitor was performed on the Cardiosens machine. Estimated: total number of supraventricular and ventricular extrasystoles (VE) per day and their distribution during the day, the presence of paroxysms of ventricular and supraventricular tachycardia. Ventricular ectopic activity was evaluated according to the classification of B. Lown, L. Wolff (1991).
All patients have gone through ECG studies in 12 assignments at a speed of 50 mm/s. According to the ECG, the heart rate (HR) and absolute QT interval (in ms), its dispersion ratio, and the adjusted QT interval were evaluated.
Materials and methods
We examined 98 patients with PFCS and concomitant type 2 diabetes mellitus, which were randomly divided into two groups: main (MG), (n = 68): 36 women and 32 men, median age of patients — 65.5 years (interquartile interval - 61-68 years old), and comparison group (CG) (n = 30): 17 women and 13 men, median age — 64.7 years old (interquartile interval —64-68 years old). Patients with PFCS and concomitant type 2 diabetes mellitus who provided informed consent were involved into the research. The monitor group (MG) was represented by 30 patients with a balanced age and sex with PFCS and concomitant type 2 diabetes mellitus.
Exclusion criteria: IIB-III stage chronic heart failure according to Strazheska and Vasylenko classification, acute coronary syndrome during the last 12 months, congenital and acquired heart diseases, complete bundle branch block, implanted cardiac pacemaker, II-III stage AV block, A-fib, autoimmune diseases, malignant oncological diseases, expressed renal, hepatic, respiratory failure, endocrine diseases (except for type 2 diabetes). General clinical characteristics of patients are shown in table 1.
Table 1.
The patients in the main group received basic therapy (BT), which included an ACE inhibitor, B-blocker, statin, antiplatelet agent, oral antidiabetic therapy and an additionally 1 capsule of 500mg twice a day of ME and 1 capsule of 400mg 3 times a day during 3 weeks of TN. Comparison group patients received only BT PFCS and type 2 diabetes mellitus drugs. In order to study the complex and isolated effects of TN and ME on the frequency of psychophysiologic disorder, main group was divided into 3 subgroups according to basic therapy supplementary treatment. The 1 subgroup (SB 1) included 22 patients who received TN, the 2 subgroup (SB 2) involved 23 patients receiving ME, and 3 subgroup (SB 3) includes 23 patients who comprehensively received ME and TN besides basic therapy. Main group and the taurine and meldonium subgroup patients with a positive response to treatment were given the
General characteristic of the examined patients (Me (IQR))
Characteristic Examined patients, n= 98
Age 64 (60-69)
Gender: female/male, n,% 50 (51.0%) /48(48.97%)
Age of diabetes, years 7.69 (7.45-8.12)
Age of IM, years 6.09 (5.35-8.02)
Body mass index, kg/m2 31.72 (27.8-39.11)
Concomitant heart failure, n, % 98 (100.0 %)
Associated arterial hypertension, n (%) 98 (100.0 %)
HOMA-IR 6.02 (5.11-6.16)
Office systolic blood pressure, mmHg 144.2 (126.7-154.5)
Office diastolic blood pressure, mmHg 87.45 (86.7-88.37)
C-reactive protein, mg/l 3.74 (3.12-5.11)
Glycosylated hemoglobin, % 7.92 (6.16-8.3)
phenylalanine + tyrosine/methionine 49.11(25.4-32.1)
Taurine/Alanine 0.031 (0.021-0.040)
conditional name of the responders. Patients without dynamics or negative response to treatment received the conditional name of non-responders. The criteria for responding to treatment were Holter ECG monitoring data: 50% reduction in total ventricular extrasystoles, 90% reduction in paired ventricular extrasystole frequency, disappearance of ventricular tachycardia jogging, reduction of episodes of painless myocardial ischemia to 3 and less times a day, and total duration of ischemia per day is less than 40 minutes (criteria of effectiveness of anti-rhythmic therapy according to Horowitz and data of VI National Cardiology Congress of Ukraine) [5].
Statistical analysis of the data was performed using SPSS, MedStat, EZR packages. Checking the normality of the parameter distribution was evaluated using the Shapiro-Fork W-test. Continuous values were compared using the Mann - Whitney U test, since their distribution was different from normal. Quantitative data are presented as Me (IQR), where Me is the median, IQR is the interquartile interval (first and third quartiles). Dunn index was used to make multiple comparisons.
We used the binary logistic regression method with odds ratio (OR) and 95% confidence interval (CI) to study the relationship between the development of positive response to treatment and predictors. Potential predictors are amino acids that could be identified as independent predictors of the development of a positive response to treatment were determined using step-by-
step logistic regression analysis of multifactorial models. Each model included a separate amino acid or ratio between amino acids that compete for entry through the cell membrane. When developing the models we considered demographic, clinical, anamnestic, instrumental, and lab risk factors. Receiver Operator Characteristic (ROC) analysis was used to determine the quality of each regression model and calculate its sensitivity and specificity, as well as to determine the area for the ROC curve (AUC).
There were no statistically significant differences between responders and non-responders within the same subgroup and when comparing different subgroups of patients by the frequency of recording of rhythm disturbances and conductibility at the beginning of the study.
Results and discussions
Multivariative logistic regression analysis with step-by-step indexing and ROC analysis showed that the initial taurine/alanine ratio was an amino acid marker, which showed correlation with the results of treatment of patients with taurine, meldonium and mel-donium+ other taurine regardless of the presence of other factors that significantly differentiated the defendants and non-responders of this group.
The value of the taurine/alanine ratio < 0.042 (AUC = 0.818; 95% CI 0.033-0.045) in blood serum was characterized by a sensitivity of 81.8% and specificity of 88.0% in predicting a positive response in patients who received taurine (Fig. 1).
Specificity
Figure 1. ROC curve of the positive response to taurine treatment from baseline taurine/alanine in the blood of patients with PFCS and type 2 diabetes mellitus.
In the meldonium subgroup, the positive response to treatment was significantly correlated with the value of the taurine/alanine blood ratio. The 0.043 taurine/alanine level was characterized by high sensitivity (80.77%) and specificity (88%) and high model quality (AUC = 0.845; CI 0.027-0.045) (Fig. 2).
Specificity
Figure 2. ROC curve of the positive response to treatment with meldonium from baseline taurine/alanine in the blood of patients with PFCS and type 2 diabetes mellitus.
The value of the taurine/alanine ratio < 0.048 (AUC = 0.949; 95% CI 0.039-0.054) in blood serum was characterized by a sensitivity of 90.9% and a specificity of 96.55% in predicting a positive response in patients who received the taurine and meldonium complex (Fig. 3)
Figure 3. ROC curve ofpositive response of taurine and meldonium treatment to baseline taurine/alanine ratio in blood of patients with PFCS and type 2 diabetes mellitus.
In the taurine and meldonium subgroup, the positive response to treatment was significantly correlated with the value of the tyrosine + phenylalanine/methionine ratio (Table 5). Tyrosine + phenylalanine/methionine> 34.41 was characterized by high specificity (92.59%) and moderate sensitivity (58.33%) and lower model quality compared to Tauline/Alanine (AUC = 0.745; CI 28.27-35, 45) (Fig. 4).
Figure 4. ROC curve of the positive response to taurine and meldonium treatment on baseline tyrosine + phenylalanine/methionine in blood of patients with PFCS and type 2 diabetes mellitus.
Discussion of the results
The results are explained by the mechanisms of competitive inhibition of the entry of amino acids into the cell. To maintain the appropriate amino acid transportation a certain ratio of the concentration of K + and Na + is required; low and especially high ions concentrations inhibit the accumulation of amino acids and tissue sections, and thus they are inhibitors of amino acid transportation. Alanine competes to enter into the cell by the p-system. We described the mechanisms of competitive inhibition of these amino acids and the possibility of using the Tauline/Alanine ratio for therapeutic and therapeutic purposes.
Methionine and aromatic amino acids that penetrate into the cell are direct competitors for cell penetration. Taking into account that aromatic amino acids are not absorbed on condition of ischemia and methio-nine is used in ischemia as a donor to methyl groups, the decrease of this coefficient is an important indicator of the effect of metabolic therapy on myocardium [3, 23, 25].
Conclusions
The effectiveness of cardio-protective therapy with meldonium and taurine depends on the ratio of individual blood amino acids involved in the processes of metabolic action and ischemic myocardial changes. The positive effect of meldonium and taurine is associated with a lower baseline plasma taurine/alanine ratio (< 0.043). Patients who meet this criterion, it is advisable to prescribe a complex of taurine + meldonium besides the basic therapy. The administration of the taurine + meldonium supplement in addition to basic therapy is also appropriate for patients with baseline tyrosine + phenylalanine/methionine in blood plasma > 34.41.
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РАЗВИТИЕ ЗДРАВООХРАНЕНИЯ И МЕДИЦИНСКОЙ НАУКИ В УФИМСКОЙ ГУБЕРНИИ НА ПЕРЕЛОМЕ ЭПОХ (КОНЕЦ XIX—НАЧАЛО XX ВВ.)
Караванова О.А.
THE DEVELOPMENT OF HEALTH AND MEDICAL SCIENCES IN UFA PROVINCE AT THE TURN OF EPOCHS (END OF XIX—BEGINNING OF XX CENTURIES)
Karavanova O.
Аннотация
В статье рассмотрены основные аспекты истории развития медицины в Уфимской губернии на рубеже веков — в конце XIX—начале XX вв. Отражена история становления здравоохранения и системы медицинской помощи, крупные эпидемии, описаны лечебные и аптекарские учреждения, органы управления, учреждения осуществляющие подготовку медицинских кадров, в динамике приведена численность и кадровый состав работников.
Abstract
The article describes the main aspects of the history of development of medicine in Ufa province at the turn of the century in the late nineteenth and early twentieth centuries, Reflected the history of the formation of health and medical care system, major epidemic, described medical and pharmaceutical companies, governments, institutions engaged in training of medical personnel in the dynamics of the given number and composition of workers
Ключевые слова: Уфимская губерния, здравоохранение, история медицины, Башкирская энциклопедия
Keywords: Ufa province, health, history of medicine, Bashkir encyclopedia
