128 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 dOI 10.11603/IJMMR.2413-6077.2019.2.10901 pOSITIVE EFFECT OF ENTEROSORpTION IN DOXORUBICIN-INDUCED CARDIOHEMODYNAMICS ALTERATION *O.O. Shevchuk1, G.V. Portnichenko2, T.Y. Lapikova-Bryginska2, S.V. Goncharov2, V.G. Nikolaev3, V.E. Dosenko2 1 – I. HORBACHEVSKY TERNOPIL NATIONAL MEDICAL UNIVERSITY, TERNOPIL, UKRAINE. 2 – O.O. BOGOMOLETZ INSTITUTE OF PHYSIOLOGY OF THE NATIONAL ACADEMY OF SCIENCE OF UKRAINE, KYIV, UKRAINE. 3 – R.E. KAVETSKY INSTITUTE OF EXPERIMENTAL PATHOLOGY, ONCOLOGY AND RADIOBIOLOGY OF THE NATIONAL ACADEMY OF SCIENCE OF UKRAINE, KYIV, UKRAINE. Background. Anthracycline antibiotics are one of the most effective anti-cancer drugs, but their cardiotoxicity what limits its therapeutic use. Objective. To analyze the efficiency of enterosorption in doxorubicin-induced cardiohemodynamics violation. Methods. Subchronic doxorubicin toxicity was modeled by injecting the anthracycline antibiotic intra- peritoneally at a dose of 5 mg/kg once a week for 4 weeks, in total 20 mg/kg. Male Wistar rats were randomly distributed into 3 groups: control; DOX-group and DOX + enterosorbent C2 rats (γ=0.18 g/cm3, BET area 2162 m2/g). Cardiohemodynamics was studied by the Millar Instruments, heart morphometry – by Avtandilov’s method. Results. Mortality rate in DOX-group was 25%. Ejection fraction and Stroke work indices were lower compared to the control group, preload adjusted maximal power decreased by 57.6%, minimum volume and end-systolic volume increased by 76,2 and 67.5% respectively. End-systolic stiffness of left ventricle (Emax) as well as arterial elastance (Ea) and end-systolic pressure had tended to decrease. Indices of left ventricle (LV) volume at systole increased: V@dPdtmax – by 73.3%, V@dPdtmin – by 81.9%. End-diastolic volume increased by 54.6%. As for the dPdtmin, and Tau constant we observed the slight tendency to its decline. Endocardial surface of LV increased by 42.7%, Planimetric Index – by 40.4% compared to the control group of rats. In DOX+C2 group mortality rate was 18.75%. We observed the strong tendency to normalization of the main indices compared to the DOX group and shrinking of the LV. We want to underline the positive trends especially in Ejection Fraction (from 39.62±10.50% to 46.23±11.46%) and Stroke Work (from 6406.50±3345.83 to 10363.14±7329.55 mmHg×uL) as important indicators of the effectiveness of cardiac pump function. Conclusions. Enterosorption demonstrated positive impact on the doxorubicin-induced violated cardiohemodynamics and decreased the mortality rate. It is a ground for further investigations. KEY WORDS: doxorubicin-induced subchronic toxicity; heart damage; enterosorption; cardiohemodynamics parameters. *Corresponding author. Oksana Shevchuk, associate profe- ssor, Pharmacology and Clinical Pharmacology Department, I. Horbachevsky Ternopil National Medical University, Maidan Voli, 1, Ternopil 46001, Ukraine. E-mail: shevchukoo@tdmu.edu.ua Introduction Anthracycline antibiotics are widely used to treat many types of malignancies because of their high efficacy. But, also, they are cardiotoxic, what limits their therapeutic use and cumulative dose [1,2]. Doxorubicin (Adriamycin, a derivative of rubomycin – 14-hydrorubomycin) is a part of chemotherapy schemes for treatment of breast and prostate cancer, solid tumors in children, sarcomas, and others. Multiple mechanisms of heart damage by anthracyclines are recognized. Oxidative stress and generation of reactive oxygen species (ROS) by “anthracycline-iron” complex; cardiac muscle’s accumulation of highly reactive alcoholic metabolite doxoru- bicinol (DOXol); cytokines disturbances; as a consequence of endogenic intoxication and bacterial translocation because of mucositis – are only a few possible ways of cardiomyocytes injury [3–7]. Till today there are no definite and 100% efficient methods for prevention and treatment of anthracyclines-induced cardiotoxicity. Iron- chelating agent dexrazoxane was implemented into protocols based on its capability to prevent free radical release [8,9]. But there are some facts that this agent could decrease the efficacy of anti-cancer chemotherapy [10]. That is why the search of effective means to ameliorate the cardiotoxicity of anthracyclines, which do not International Journal of Medicine and Medical Research 2019, Volume 5, Issue 2, p. 128-136 copyright © 2019, TNMU, All Rights Reserved O.O. Shevchuk et al. 129 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 O.O. Shevchuk et al. attenuate the anti-tumor activity of drugs, re- mains actual. Sorption Detoxification is a well­ known method for cleaning of body fluids from toxic endogenous or exogenous compounds. The most widely used types of this method are the purification of blood or its components (hemosorption), oral administration of sorption materials (enterosorption), and application- sorption therapy of wounds and burns [11]. Our previous studies with enterosorbents Carboline and carbon granular oral adsorbent C2 de- monstrated promising results to alleviate the side effects caused by cytostatic agents mel- phalan and cisplatin (bone marrow suppression, gastrointestinal toxicity, testes damage, etc.) [12–15]. Enterosorbent C2, which has optimized and shifted to mesopores porous structure, in combination with an officinal biosimilar of gra­ nulocyte colony­stimulating factor (filgrastim) ameliorated hematologic toxicity and oxidative stress indexes much better than each of these preparations alone [16]. The objective of this study is the assess- ment of the capability of carbon granular oral adsorbent C2 to diminish the doxorubicin- induced heart damage. Methods Materials Doxorubicin hydrochloride (Doxorubicin Teva 10 mg/5ml, concentrate for solution for infusion, TEVA Pharmachemie, the Netherlands) was used for experiments. Carbon oral adsor- bent C2 was specially designed at the Depart- ment of Means and Methods of Sorption The- rapy of R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology (IEPOR). Parameters of enterosorbent C2 are next: bulk density γ=0.18 g/cm3, granules with a diameter of 0.15–0.25 mm, the porous structure of C2 is well developed and shifted toward mesopores, which surface is 565 m2/g. BET (Brunauer- Emmett-Teller) surface area is 2162 m2/g. Animal studies All experiments were carried out with male Wistar rats, 180-220 g of primary weight, which were reared at TNMU animal facility (Ternopil, Ukraine). All procedures were done according to the local bioethical committee guidelines which conform to the rules and requirements of European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (1986) and EU Direc­ tive on the Use of Animals for Research Direc- tive 2010/63/EU. A common light-dark cycle was maintained for rats and fed on common rodent chow diet with tap water ad libitum, according to the guidelines for animal care. A well-documented regimen was used for the induction of heart damage by doxorubicin [17]. Animals were randomly assigned to 3 groups: 1) control group (n=7); 2) rats treated with DOX (DOX­group) (n=16); 3) rats treated with both DOX and carbon enterosorbent C2 (DOX+C2) (n=16). Subchronic doxorubicin toxicity was mode- led by injecting the anthracycline antibiotic intraperitoneally at a dose of 5 mg/kg once a week for 4 weeks, in total 20 mg/kg [17]. The animals serving as control received the same volume of saline intraperitoneally once a week for a total of 4 weeks. Newly designed carbon oral adsorbent C2 was given into the stomach via a custom rigid tube once a day at a dose of 5 ml per kg (or 1 ml for each 200 g of rat body weight; or 900 mg of the dry mass of the enterosorbent). We started enteral sorption therapy the next day after the first injection of Doxorubicin. The sorbent was given as a sus- pension in an appropriate volume of distilled water. The rats of the control group received an equal volume of distill water. On the days of doxorubicin injection and one day before it, the enterosorbent was not given to avoid any pharmacokinetics disruption. Cardiohemodynamics measurements For the direct cardiac function evaluation, we used Millar pressure-volume (P-V) system (MPVS-300, Millar Instruments, Houston, TX, USA). On the 29th day of the experiment counting from the first injection of doxorubicin, under urethane general anesthesia (1.5 g/kg) the right carotid artery was exposed and ligated distally, the artery was clamped and incised, and a 0.5 cm long 90 PE tube was inserted as a catheter guide. A 2-Fr Mikro-Tip catheter (SPR- 838, Millar Instruments, Houston, TX, USA) was advanced through the guide into the LV under pressure control; a ligature was then tightened around the catheter to avoid blood loss [18]. After stabilization for 5 min, signals were continuously sampled at a sampling rate of 1000 samples/sec by the MPVS-300 system, recorded, and displayed on a personal computer by the PowerLab System and ChartTM v.5.4.2 software (ADInstruments, Millar Instruments) for 15-20 min. The relation of pressure and volume of the left ventricle was performed by software PVAN 3.6 (AD Instruments, Millar Instruments) with the conversion of relative volume units (RVU) into absolute one (equation slope 20,25×RVU – 130 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 intercept 29,05). The Millar P-V System simulta- neously and continuously measures left vent- ricle (LV) pressure (P) and volume (V) from the beating heart, producing characteristic PV loops readings of which a variety of cardiovascular parameters, such as heart rate (HR), cardiac output (CO), stroke volume (SV), ejection fraction (EF), stroke work (SW), dP/dtmax, and dP/dtmin are derived. End-systolic pressure (ESP), end-systolic volume (ESV), end-diastolic pressure (EDP), end-diastolic volume (EDV), stroke volume (SV), stroke work (SW), maximum dP/dt (dPdtmax), minimum dP/dt (dPdtmin), tau, maximum dV/dt (dVdtmax), minimum dV/dt (dVdtmin), maximum pressure (Pmax), minimum pressure (Pmin), maximum volume (Vmax), and minimum volume (Vmin) were also analyzed. Morphometrics of the heart To estimate chronic changes of the shape and size, the hearts of the rats were used for measuring and evaluating of the planimetric index. For indirect planimetry of the endocardial surface of the rats’ hearts, ventricles were taken accordingly to Avtandilov G.G. method[19] in Esypova I.K. et al. modification [20]. We measu­ red the endocardial surfaces of the left (ELV) and right ventriculi’s wall area (ERV). Planimetric index (PI) was calculated as: PI=ELV÷ERV. where ELV is the endocardial surfaces of the left ventricle wall area and ERV is the endocardial surfaces of the right ventricle wall area. Statistical analysis The normality of data distribution was tested using Kolmogorov-Smirnov test, homo- geneity of variance – Levene’s test. Mann- Whitney test and One-way ANOVA was applied to test the differences between the groups. Statistical analysis was performed using Micro- soft Excel ХР (USA) and Statistica 10.0 (StatSoft Inc., USA). Differences were considered signi- ficant if the probability of Type I error was less than 0.05. P<0.05 was considered significant. Results In DOX-group the number of prematurely deceased rats was four, in DOX+C2 group – three rats died before the end of the experiment. All abovementioned animals died after the 4th injection of doxorubicin during the last week of the experiment. Among survived rats we ob- served typical clinical signs of heart failure: rats showed clear signs of dyspnea, from mild to severe ascites, different stages of hydrothorax and liver enlargement; their common activities were reduced compared to the rats of the control group. Those sings had less intensity compared to the untreated group of animals. The pump function of the heart was ana- lyzed by next parameters: ejection fraction, stroke volume and stroke work and cardiac output, as well as maximal power and preload adjusted maximal power (PaMP) (table 1). These parameters are load-dependent and con sequently represent poor contractility indi- ces. Increased cardiac output, high heart rate as well as stroke volume are the typical signs of cardiac dysfunction and followed systemic hemodynamic changes and our results sup- posed it. It was a strong tendency for increasing of the all abovementioned indices, but enteral sorption therapy partly disrupts it. Ejection fraction in DOX-group rats was lower, but in the group DOX+C2, we see the tendency to its normalization. The same tendency was for the stroke work: from 6406.50±3345.83 in rats, which received injections of doxorubicin, it increased to 10363.14±7329.55 mmHg×uL for rats which got oral adsorbent concomitantly. While the index in rats of the control group was 7036.43±5036.46 mmHg×uL. Minimum volume increased by 76,2%, end- systolic volume – by 67.5%. For both indices, we observed the tendency for decreasing by oral adsorbent therapy, but they did not come close to the numbers of control group rats. In the rats of DOX-group the index of maximal power did not change significantly, but the strong tendency to its decreasing we saw, while preload adjusted maximal power (PaMP) was lower by 57.6% compared to the control group. Enteral sorption therapy promoted the tendency to normalization of the indices. End-systolic stiffness of left ventricle (Emax) had a strong tendency to decreasing from 4.55±2.93 to 2.74±2.02 (what means that left ventricle was dilated and lost end-systolic elastance), while carbon oral adsorbent C2 increased this index to 5.30±0.44. Specific parameters as the volume at the point of maximal speed of pressure change (V@dPdtmax) and volume at the point of maximal speed of pressure decline (V@dPdtmin) are used for assessment of LV volume at systole. So, V@dPdtmax increased by 73.3%, while V@dPdt min – by 81.9%. During diastole, the myocardium stops shortening and generating force and relaxes. Diastolic function was analyzed by changes of end-diastolic pressure and volume, the peak rate of pressure decline (dPdtmin) – isovolumic relaxation, constant Tau by Weiss method (τw). O.O. Shevchuk et al. 131 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 O.O. Shevchuk et al. End-diastolic volume increased by 54.6% in the group of rats, which received doxorubicin com- pared to the control rats. As for the dPdtmin, we observed a slight tendency to its decline, as well as for the Tau constant. After 4 injections of Doxorubicin on 29th day of the experiment, the endocardial surface of the left ventricular wall area increased by 42.7% (p<0.001) compared to control group of rats (table 2). At the same time, there were no changes in the right ventricular wall area. In rats which received enterosorption together with doxorubicin, the endocardial surface of the left ventricular wall area index decreased Table 1. Cardio-hemodynamics indices in rats, which received doxorubicin and enteral sorption therapy with oral carbon adsorbent C2. Index Control group DOX group DOX + С2 group HR (min−1) heart rate 321.0±43.89 356.64±48.82 378.38±33.86 Maximum Volume (uL) 146.79±13.08 232.76±76.58 236.68±102.07 Minimum Volume (uL) 78.27±15.17 137.93±46.96* 126.05±35.68 End-systolic Volume (uL) 84.87±17.73 142.16±47.56* 130.76±36.68 End-diastolic Volume (uL) 142.56±11.36 220.44±70.94* 223.75±85.04 Maximum Pressure (mmHg) 116.24±21.53 102.0±22.51 111.85±14.35 Minimum Pressure (mmHg) 4.97±3.89 4.15±3.39 2.10±1.65 End-systolic Pressure (mmHg) 109.57±25.12 96.22±24.07 104.58±16.72 End-diastolic Pressure (mmHg) 9.10±4.28 6.72±4.54 5.99±3.77 Stroke Volume (uL) 68.52±21.34 94.835±39.90 120.88±78.45 Ejection Fraction (%) 46.15±11.83 39.62±10.50 46.23±11.46 Cardiac Output (uL/min) 22222.85±8424.99 33103.55±13814.04 44721.45±28511.89 Stroke Work (mmHg×uL) 7036.43±5036.46 6406.50±3345.83 10363.14±7329.55 Arterial Elastance (Ea), (mmHg/uL) 2.25±0.71 1.06±0.49 1.11±0.56 dPdt max (mmHg/sec) 11758.0±5232.28 9897.43±3142.76 12769.50±2861.17 dPdt min (mmHg/sec) -7312.86±2477.79 -7062.50±1742.62 -8928.12±3274.57 dVdt max (uL/sec) 2811.14±1048.07 4783.57±1703.76 4489.87±2985.50 dVdt min (uL/sec) -3345.57±1283.04 -3893.5±1345.52 -4751.13±2491.48 P@dVdt max (mmHg) 38.27±32.11 40.16±35.79 34.62±36.27 P@dPdt min (mmHg) 88.67±50.41 64.69±13.78 74.00±21.68 V@dPdt max (uL) 124.90±25.62 216.46±76.45* 228.02±102.85* V@dPdt min (uL) 79.91±15.49 145.33±52.64* 129.76±36.71 Tau(W) (msec) 12.69±5.87 11.41±5.01 9.25±1.96 Tau(G) (msec) 18.34±11.18 13.80±5.68 11.90±3.39 Maximal Power (mWatts) 43.89±34.61 38.94±18.71 57.61±32.30 Preload adjusted maximal power, PaMP (mWatts/µL^2) 20.81±15.88 8.82±4.78* 12.38±5.77 Emax 4.55± 2.93 2.74±2.02 5.30±0.44 Notes. The data are expressed as means (M) ± standard deviation (SD);* – p<0,05 comparing to control group; dPdtmax – peak rate of pressure rise; dPdtmin – peak rate of pressure decline; dVdtmax – peak rate of volume rise; dVdtmin – peak rate of volume decline; P@dVdtmax – Pressure at dV/dt max; P@dPdtmin – Pressure at dV/dtmin; V@dPdtmax – Volume at dP/dtmax; V@dP/dtmin – Volume at dP/dtmin; Tau (G) – relaxation time constant calculated by Glantz method (regression of dP/dt versus pressure); Tau (W) – relaxation time constant calculated by Weiss method (regression of log(pressure)); Emax – end-systolic elastance. Table 2. The influence of enterosorption on morphometric indexes of the heart ventricles in subchronic doxorubicin toxicity in rats. Index Control group DOX-group DOX+С2 group The endocardial surface of left ventricular wall area, mm2 118.0±4.45 168.4±7.63* 132.6±3.06*, ** The endocardial surface of right ventricular wall area, mm2 132.2±6.27 134.8±6.54 137.8±4.88 Planimetric index (PI) 0.894±0.010 1.25±0.032* 0.965±0.022** Notes: The data are expressed as means (M) ± standard error (SE). p<0.05 compared to * – control group; ** – DOX-group. 132 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 by 21.3% compared to the DOX group, but it was still larger than in rats of the control group. Doxorubicin injections increased the Plani- metric index (PI) the by 40.4% compared to the control group (from 0.89±0.01 to 1.25±0.03), while in DOX+С2 group it decreased by 22.8% (0.96±0,02, p<0.001). Discussion Our study deals with the effect of entero- sorption on doxorubicin-associated cardiac toxicity. Doxorubicin’s use in patients is limited by its cardiac toxicity. Today a new subspecialty appeared – cardio-oncology, which focuses on prevention, detection, monitoring, and treat_ ment of cardiovascular pathology during anti- cancer chemotherapy [21]. It is a marker of the high importance of this problem because long term survival of childhood cancers is more than 70% for now [6] and continued to increase [22]. Strong links between cancer and heart disease are recognized, that is why a clinical need for optimized cardio-oncology patient management is growing. Among anti-cancer agents, the most capable drugs to cause the dilative cardio- myopathy are anthracyclines and cyclophos- phamide [16,23]. Dose-dependent irreversible heart damage occurs in 1.7% of patients mostly via oxidative stress activation and by inhibition of transcriptions of genes, which are responsible for the synthesis of the contractile proteins [3,16]. Up to 3% of heart transplantations were done for patients because of doxorubicin therapy [6]. It is known that the prognosis of patients who develop doxorubicin-induced congestive heart failure is poor: approximately ~50% mortality in 1 year [3]. Monoclonal anti- body trastuzumab and low molecular tyrosine kinase inhibitors as sunitinib and sorafenib may cause heart damage too [23]. They modulate mitochondrial integrity, deplete ATP and lead to contractile dysfunction. But in this case, the contractile function of the left ventricle improves after drugs discontinuation [23]. We used typical widespread modeling to induce congestive heart failure in rats: four injections of DOX at the dose of 5 mg/kg for cumulative dose 20 mg/kg and got the cardio- hemodynamic disruption [17]. So, this model could be used for assessment of the capability of different substances and drugs to impact the heart systolic and diastolic function. One of the experimental morphometric methods to mea- sure and estimate the type and deepness of heart injury is weighing and weight measu- rement of different parts of the organ namely left and right ventricle with the septum (vent- ricle index, Fulton index, etc.). The planimetric method allows estimating changes of both ventricles by measuring the endocardial sur- faces area [19]. And this method is validated to estimate the chronic changes of the heart mor- phology, while cardiohemodynamics violations measured by Millar Instruments are quite good for assessment of acute functional changes in heart work. A wide variety of indexes that can be quantified by analyzing pressure­volume (PV) loops have been proposed to characterize the left ventricle systolic and diastolic performance. In the present study, doxorubicin-associated cardiac dysfunction was manifested by a re- duction in cardiac systolic and diastolic hemo- dynamic function. We have shown statistically significant differences between DOX and cont­ rol groups in parameters of end-systolic and end-diastolic volumes as well as volumes at the point of maximal speed of pressure change and pressure decrease. Also, we have shown a 57.6% decrease in Preload adjusted maximal power. Doxorubicin at the cumulative dose of 20 mg per kg promoted the heart dilation, which was confirmed by increased indices of the endocardial surface of the left ventricular wall area and planimetric index. Our previous study demonstrated the decreased mass of the heart in subchronic doxorubicin toxicity. So, despite only the slight tendency of ejection fraction declining, these important changes already indicate the onset of the dilated cardio- myopathy. Such results are supported by re- search on the male New Zealand white rabbits with doxorubicin-induced heart damage [24]. So, we may conclude, that early myocardial effects of doxorubicin-induced cardiotoxicity are presented. We may talk about early stages of dilated cardiomyopathy with still preserved ejection fraction, but with clinical signs of congestion in survived rats – non-failing dilated left ventricle in survived animals. Our results are confirmed by the study of Lodi M. et al. [25]: A significantly reduced ejection fraction was seen on day 80 only. They modeled cardio- myopathy by 6 IV injection of DOX at the dose of 1.5 mg/kg on the 8th, 11th, 14th, 17th, 20th and 23rd days of the experiment [25]. Also, the results of our histological examination of heart tissues presented revealed loss of myofibrils and striations, as well as cytoplasmic edema. Our previous study demonstrated that ente- rosorption with C2 ameliorates the morpho- logical sings of heart damage [26]. Also, we O.O. Shevchuk et al. 133 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 O.O. Shevchuk et al. observed improvements of hematological pa- rameters, kidney’s function and decrease of endogenous intoxication markers. Those data are in press. It is important to mention that the conco- mitant course of enterosorption during this experiment decreased the mortality rate. In rats which received doxorubicin, it was 25% (4 rats from 16), while at the DOX+C2 group – 18.75% (3 rats from 16). DOX+C2 rats’ group has shown a statistically significant difference compared to the control group in the parameter of volume at the point o f m a x i m a l s p e e d o f p re s s u re c h a n g e . V@dPdtmax increased by 82.6%. All 26 parameters of cardiohemodynamics were altered in rats which received doxorubicin at the total dose of 20 mg/kg. More than a half (14 parameters) among them demonstrated tendency to normalization under the influence of enteral sorption therapy. Especially we want to notice the positive tendency in indices of Preload adjusted maximal power, PaMP (from 8.82±4.78 to 12.38±5.77 mWatts/µL^2), Maximal Power (from 38.94±18.71 to 57.61±32.30 mWatts, and it was even higher than in the control group – 43.89±34.61 mWatts), Stroke Work (from 6406.50±3345.83 to 10363.14±7329.55 mmHg×uL, while the control group index was 7036.43± 5036.46 mmHg×uL) and Ejection Fraction from 39.62±10.50% to 46.23±11.46%, when in the control group it was 46.15±11.83%). Conclusions Doxorubicin at the total dose of 20 mg/kg caused pronounced violation of cardio hemo- dynamics. Systolic indices as Ejection fraction, stroke work, end-systolic elastance (Emax), end- systolic pressure – all these indices demonstrated a tendency to decline, preload adjusted maxi_ mal power (PaMP) was lower by 57.6% compared to the control group. It is a marker of weaker pump function and poor contractility of the heart. Morphometry showed dilation of the left ventricle and increased planimetric index. At the same time, the diastolic indices were disrupted too. End­diastolic volume significantly increased by 54.6%, the index of peak rate of pressure had a tendency for declining, as well as Tau(w). The indices of volume at the point o f m a x i m a l s p e e d o f p r e s s u r e c h a n g e (V@dPdtmax) and volume at the point of maximal speed of pressure decline (V@dPdtmin) sig- nificantly increased in rats, which received doxorubicin. It confirms the diastolic dysfunction presence. Enteral sorption therapy mostly normalized and improved violated indices and decreased the rate mortality of rats. We observed shrin- king of the endocardial surface of the left ventricular wall area by 21.3% and decreasing of Planimetric Index. Those results demonstrate that enterosorption could prevent remodeling of the heart chambers. Our cardiohemodynamics investigations included more than 20 para- meters and though mostly they are not statis- tically significant we want to underline the positive trends in DOX+C2 rats comparing to DOX-group, especially in Ejection Fraction and Stroke Work parameters as they are the im- portant indicators of the effectiveness of cardiac pump function. Such results could be explained by the fact that measurement of hemodynamics was done one week later after the last 4th injection of doxorubicin, and we observed the consequences of mechanisms of adaptation in survived rats. Our research demonstrated promising results of the efficiency of carbon granular oral adsorbent C2 to ameliorate the doxorubicin- associated cardiohemodynamics changes and are the ground for further future investigation of different combinations of enterosorption and cardio-tropic drugs. Funding This research received no external funding. Conflict of Interests The authors declare no conflict of interest. Author Contributions Shevchuk O.O. – investigation, conceptua- lization, resourses, writing – original draft; Portnichenko G.V. – formal analysis, visualization, investigation, writing – original draft, data curation, Lapikova-Bryginska T.Y. – investigation, data curation, Goncharov S.V. – investigation, data curation; Nikolaev V.G. – conceptualization, project administration, writing (review and editing), supervision; Dosenko V.E. – project administration, writing (review and editing), supervision. 134 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 позитиВниЙ ВплиВ ентеросорБціЇ на порушення кардіогемодинаміки, спричинені доксоруБіцином О.О. Шевчук1, Г.В. Портніченко2, Т.Є. Лапікова-Бригінська2, С.В. Гончаров2, В.Г. Ніколаєв3, В.Є. Досенко2 1 – ТЕРНОПІЛЬСЬКИЙ НАЦІОНАЛЬНИЙ МЕДИЧНІ УНІВЕРСИТЕТ ІМЕНІ І.Я. ГОРБАЧЕВСЬКОГО, ТЕРНОПІЛЬ, УКРАЇНА 2 – ІНСТИТУТ ФІЗІОЛОГІЇ ІМЕНІ О.О, БОГОМОЛЬЦЯ НАН УКРАЇНИ, КИЇВ, УКРАЇНА 3 – ІНСТИТУТ ЕКСПЕРИМЕНТАЛЬНОЇ ПАТОЛОГІЇ, ОНКОЛОГІЇ І РАДІОБІОЛОГІЇ ІМЕНІ Р.Є. КАВЕЦЬКОГО НАН УКРАЇНИ, КИЇВ, УКРАЇНА Вступ. Кардіотоксичність протипухлинних лікарських засобів, і особливо антрациклінових антибіотиків, є одним з лімітуючих факторів ефективного лікування злоякісних новоутворів. Мета. Дослідити можливості ентеросорбції для пом’якшення кардіогемодинамічних змін, викликаних доксорубіцином в експерименті. Методи. Субхронічна доксорубіцинова токсичність моделювалася чотирьохкратним введенням доксорубіцину інраперитонеально в дозі 5 мг/кг один раз на тиждень протягом 4 тижнів у сумарній кумулятивній дозі 20 мг/кг. Щури були рандомізовані у 3 групи: контроль, група тварин, що отримувала доксорубіцин (DOX-група) та групу, котра окрім останнього отримувала ентеросорбент С2 (γ=0.18 г/см3, BET – 2162 м2/г). Параметри кардіогемодинаміки вивчалися за допомогою Millar Instruments, морфомтричні зміни серця – за методом Автанділова. Результати. Летальність у DOX-групі склала 25%. Показники фракції викиду та ударної роботи серця знижувалися порівняно з показниками контрольної групи. Показник максимальної потужності, зрівноваженої на переднавантаження був достовірно нижчим на 57,6%, а мінімальний об’єм та кінцево- систолічний об’єм зросли на 76,2 та 67,5%, що свідчить про розвиток застійних явищ. Показники V@dPdtmax зросли на 73.3%, V@dPdtmin – на 81.9%. Кінцево-діастолічний об’єм був вищим на 54.6%. Спостерігалася тенденція до зниження dPdtmin та Tau константи. Ендокардіальна поверхня лівого шлуночка зросла на 42,7%, а планіметричний індекс – на 40,4%. У групі DOX+C2 летальність склала 18,75%. Спостерігалася виражена тенденція до нормалізації усіх показників. Особливо ми хочемо підкреслити позитивний ефект застосування вуглецевого ентеросорбента С2 на показники фракції викиду (з 39.62±10.50% до 46.23±11.46%) та ударної роботи (з 6406.50±3345.83 до 10363.14±7329.55 мм.рт.ст×мкл) як важливих показників насосної функції серця. Висновки. В статті наведені дані, котрі демонструють здатність ентеральної сорбційної терапії зменшувати зрушення показників кардіогемодинаміки, спричинені введенням доксорубіцину. Окрім цього, ентеросорбція сприяла зменшенню показника летальності піддослідних тварин. КЛЮЧОВІ СЛОВА: cубхронічна доксорубіцинова токсичність; пошкодження серця; ентеросорбція; параметри кардіогемодинаміки. Відомості про авторів Шевчук Оксана – канд. мед. наук, доцент кафедри фармакології з клінічною фармакологією, Тернопільський національний медичний університет імені І.Я. Горбачевського, Тернопіль , Україна Портніченко Георгій – канд. біол. наук, відділ загальної та молекулярної патофізіології, Інститут фізіології імені О.О.Богомольця НАН України, Київ, Україна. Лапікова-Бригінська Тетяна – відділ загальної та молекулярної патофізіології, Інститут фізіології імені О.О.Богомольця НАН України, Київ, Україна. Гончаров Сергій – відділ загальної та молекулярної патофізіології, Інститут фізіології імені О.О.Богомольця НАН України, Київ, Україна. Ніколаєв Володимир Григорович – чл.­кор. НАН України, професор, д­р мед. наук, завідувач відділу засобів та методів сорбційної терапії, Інститут експериментальної патології, онкології і радіо­ біології імені Р.Є. Кавецького НАН України, Київ, Україна. Досенко Віктор Євгенович – професор, д­р мед. наук, завідувач відділу загальної та молекулярної патофізіології інституту фізіології імені О.О. Богомольця НАН України, Київ, Україна. Information about the authors Oksana O. Shevchuk – MD, Ph.D., Pharmacology and Clinical Pharmacology Department, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. ORCID 0000­0003­2473­6381, e­mail: shevchukoo@tdmu.edu.ua Georgii V. Portnichenko – Ph.D., Department of General and Molecular Pathophysiology, Bogomoletz Institute of Physiology of the National Academy of Science of Ukraine, Kyiv, Ukraine. ORCID 0000­0001­8834­3013, e­mail: krissaegrim1@gmail.com O.O. Shevchuk et al. 135 B io m e d ic a l S c ie n c e S iSSn 2413-6077. iJmmR 2019 Vol. 5 issue 2 O.O. Shevchuk et al. Tetiana Y. Lapikova-Bryhinska – Department of General and Molecular Pathophysiology, Bogomoletz Institute of Physiology of the National Academy of Science of Ukraine, Kyiv, Ukraine. ORCID 0000­0003­3405­6566, e­mail: tlapikovabr@gmail.com Sergii V. Goncharov – Department of General and Molecular Pathophysiology, Bogomoletz Institute of Physiology of the National Academy of Science of Ukraine, Kyiv, Ukraine. 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