The cardiotropic activity of etmaben, a malonic acid derivative, has been confirmed by a number of studies. The possibility of using empagliflozin in chronic heart failure has been proven in a number of preclinical and clinical studies. In this study, the efficacy of the drugs in monotherapy and combined use regimens is compared using a model of experimental chronic heart failure in rats. The most effective treatment regimen was found to be etmaben; its combination with empagliflozin led to a decrease in effectiveness, regardless of which of these drugs was the starting drug.

Неалкогольная жировая болезнь печени — чрезвычайно распространенное мультисистемное метаболическое заболевание, для лечения которого до сих пор не разработаны лекарственные средства с достаточной эффективностью и безопасностью. Целью настоящей работы стала оценка гепато- и нейропротекторного потенциала фиксированной комбинации фармакологических веществ: янтарной кислоты (88,3 мг/кг/сут), метионина (70,64 мг/кг/сут) и рибофлавина (1,06 мг/кг/сут) в сравнении с адеметионином (211 мг/кг/сут) при курсовом (3 мес) введении внутрь мышам-самцам с экспериментальным неалкогольным стеатогепатитом. Экспериментальный неалкогольный стеатогепатит у мышей сопровождался снижением выживаемости (относительный риск летального исхода 10,05, p < 0,01), характерными изменениями морфологии печени (стеатоз, баллонная дистрофия гепатоцитов, патологическая клеточная инфильтрация) и биохимических показателей крови (увеличение активности аланинаминотрансферазы, p < 0,01), индукцией маркеров фиброгенеза и стеатоза (гиалуронансинтазы-2 (HAS2), стеароил-коэнзим А-десатуразы (SCD1), p < 0,05). Также наблюдали снижение общей двигательной и исследовательской активности (уменьшение скорости движения и числа заглядываний в отверстия, p < 0,05; уменьшение числа стоек, p < 0,01), рабочей памяти (снижение частоты спонтанного чередования, p < 0,05) и физической работоспособности мышей (уменьшение времени вынужденного плавания, p < 0,01). Как комбинация фармакологичесих веществ, так и препарат сравнения адеметионин обладали антицитолитическим эффектом (снижали активность трансаминаз, p < 0,05) и оказывали положительное влияние на экспрессию тканевых маркеров поражения печени (повышали экспрессию аполипопротеина А1, матриксной металлопротеиназы-9, p < 0,05; снижали экспрессию HAS2, SCD1, p < 0,05). Применение комбинации фармакологических веществ сопровождалось нормализацией состояния краткосрочной памяти (увеличивало частоту спонтанного чередования, p < 0,01) и позволяло восстановить уровень исследовательской активности мышей (повышало число заглядываний в отверстия, p < 0,05), не оказывая существенного влияния на уровень их тревожности. Ни один из исследованных вариантов фармакологического воздействия не оказывал влияния на физическую работоспособность и показатели функции нейромоторного аппарата. Таким образом, комбинация фармакологических веществ при курсовом введении обладает способностью восстанавливать морфологию и функции печени, а также оказывать влияние на сопутствующие неврологические нарушения без влияния на тревожно-подобное поведение мышей, в отличие от адеметионина. Механизмы действия и отдельные аспекты гепато- и нейротропной активности комбинации требуют дальнейшего уточнения.

Ethnopharmacological relevance: Ziziphora clinopodioides subsp. bungeana (Juz.) Rech.f. is a subshrub that is widely distributed in China, Kazakhstan, Kyrgyzstan, Mongolia, Russia, Tajikistan, Turkmenistan, and Uzbekistan. The species is used in traditional medicine for the relief of symptoms connected to cardiovascular diseases like coronary heart disease or hypertension. Aim of the study: was to validate traditional use of Z. clinopodioides subsp. bungeana for the treatment of coronary hearth diseases using in vivo models and to find active compounds responsible for the activity. Materials and methods: Multiple extracts were obtained from the aerial parts of Z. clinopodioides subsp. bungeana using maceration, liquid-liquid extraction, CO2 extraction and ultrasound-assisted extraction. Preliminary screening studies for the evaluation of the efficacy of Z. clinopodioides subsp. bungeana extracts on the model of hemic hypoxia were performed. The most effective samples were selected and included in the main study. Stage 2 of the study evaluated the cardiotropic activity of the selected extracts on a model of chronic heart failure. Preparations were administered to animals intragastrically once a day for 28 days. For the isolation of individual compounds plant material was extracted with 96% ethanol. The obtained crude extract was sequentially extracted with n-hexane and dichloromethane and separated by chromatography on a Diaion HP-20 column. The obtained fractions were further subjected to Sephadex LH-20 column chromatography and eluted isocratically with 96% ethanol (EtOH) to yield subfractions, which were further separated by preparative HPLC to obtain 13 individual compounds. Results: Extracts obtained from Ziziphora clinopodioides subsp. bungeana (Juz.) Rech.f. herb were subjected to pharmacological screening for the evaluation of their efficacy on hemic hypoxia. Based on the obtained results, out of the sixteen tested extracts two (AR and US 60%) were selected for further evaluation of their cardiotropic activity. Modeling of chronic heart failure was carried out in accordance with the following stages: 1) anesthesia with chloral hydrate at a dose of 450 mg/kg, intraperitoneally, 2) artificial ventilation of the lungs, 3) thora-cotomy, 4) modeling of permanent ischemic or ischemic-reperfusion damage. Both extracts effected the in-dicators of contraction and output, comparable to the reference drug -Monopril. Based on the extraction methods used to obtain RAF and US60 and data from the literature, it can be assumed that they contain com-pounds with medium polarity, including polyphenols and terpenoids. At the next stage three previously unde-scribed monoterpenoid derivatives - Ziziphoric acid (1), Ziziphoroside D (2) and 6 & PRIME;-malonylziziphoroside A (3), along with two previously described megastigmane glucosides - blumenol C glucoside (4), blumenol C 9-O-(6 & PRIME;-O-malonyl-beta-D-glucopyranoside (5) and two previously described monoterpenoids 7a-hydroxymintlactone (6), 7-hydroxypiperitone (7) together with six polyphenols - pinocembrine-7-O-rutinoside (8), chrysine-7-O-rutinoside (9), acacetin-7-O-rutinoside (10), luteolin-7-O-rutinoside (11), rutin (12) and rosmarinic acid (13) were isolated from Z. clinopodioides subsp. bungeana extracts. Conclusion: Our results support the traditional use of Z. clinopodioides subsp. bungeana for the treatment of coronary diseases. As a result of Z. clinopodioides subsp. bungeana extracts screening in vivo, two extracts were selected as potential cardiotropic agents. Phytochemical analysis of the plant material led to the isolation of five terpenoid derivatives, two megastigmane glycosides, five flavonoids and one cinnamic acid derivative, which could be responsible for the reported biological activity. Future experiments are required to understand the mechanisms of action for the isolated compounds.

Introduction. It is known that a number of species of the genus Cistus are used in Mediterranean folk medicine in the form of infusions and herbal teas to treat digestive problems and acute respiratory virus infection. Empirical data have accumulated that sage incense extract improves the condition of patients with chronic cholestatic liver diseases (CLDs). Currently, only ursodeoxycholic acid (UDCA) is the generally accepted drug for the treatment of most CLDs. Aim. Comparative efficacy evaluation of Cistus salviifolius extract (at 2 doses levels) compared to the reference medicine ursodeoxycholic acid Ursosan® (at a therapeutic dose) in intragastric administration to mice in a cholestasis model induced by intragastric administration of alphanaphthylisothiocyanate (ANIT) oil solution during 20 Days. Materials and methods. The cholestase model was induced by intragastric administration of an alpha-naphthylisothiocyanate oil solution to mice during 20 days. The following biochemical parameters were determined in the serum of experimental animals: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, total cholesterol, bilirubin, triglycerides, albumins. Histological analysis was performed on the liver and gallbladder. Results and discussion. Cistus salviifolius extract at a therapeutic dose of 253 mg/kg and at a dose exceeding the therapeutic dose (506 mg/kg), as well as the reference medicine of Ursodeoxycholic acid Ursosan® at a therapeutic dose of 150 mg/kg reduced the level of aspartate aminotransferase in serum increased after ANIT administration to a level of the control group without pathology. Deviations of other parameters from the control group (alanine aminotransferase, alkaline phosphatase, total protein, total cholesterol, bilirubin, triglycerides, albumins) were statistically insignificant. Histological analysis of the liver and gallbladder demonstrated that the severity of ballooning degeneration and cholecystitis were significantly reduced in groups which was treated by Cistus salviifolius extract at two doses, but not in the group with reference drug. The severity of cholestasis was poorly influenced by Cistus salviifolius extract in contrast to ursodeoxycholic acid, which was more effective for this pathology. Conclusion. The conducted study against the background of reports on the effectiveness of the Cistus salviifolius extract in clinical practice allows to recommend its use as a component of combined therapy of a patient with hepatobiliary pathology and as a pharmacoprevention in healthy people in the presence of risk factors.

Introduction. Osteoarthritis is now considered to be a slowly progressive inflammatory disease that completely affects the joint. An important role in the development of this pathology is played by inflammation of the synovial membrane and ligaments (synovitis), supplemented by constant mechanical stress. Normally, a balance of anti-inflammatory and pro-inflammatory mediators is observed in cartilage, however, under the influence of risk factors, this balance shifts towards the latter.Aim. Evaluation of the effect of a previously developed soft dosage form containing meloxicam, a purine derivative and an immunomodulator M on the level of pro-inflammatory cytokines: IL-1α, IL-1β, IL-6 and TNF-α in osteoarthritis.Materials and methods. The experiment included 25 animals, which were divided into 5 groups by simple randomization: 1 – test (gel 0.5 %), 2 –test (gel 1 %), 3 – reference (Amelotex®, gel 1 %), 4 – control (gel base); 5 – intact. Preclinical modeling of the pathology was carried out by combined injection of 0.1 ml of a mixture of complete Freund's adjuvant with a 10 % suspension of talc in isotonic sodium chloride solution in a ratio of 1 : 10 into the cavity of the hock (tarsal) joint of Brown Norvay Catholic Rats male rats. Enzyme immunoassay of animal blood serum on the 28th day of the experiment was performed using standard ELISA plate kits (Cloud-Clone Corp., USA). Statistical data processing was performed using GraphPad Prism 8.0.2 software (GraphPad Software Inc., USA), differences were considered statistically significant at p < 0.05.Results and discussion. The developed compositions contributed to a decrease in the level of pro-inflammatory cytokines (IL-1α, IL-6 and TNF-α) compared with the main and reference gel preparation. At the same time, differences were found between the effect observed from the use of the test agents (gel 0.5 %, gel 1 %) and the reference drug in terms of the effect on the level of IL-1α and TNF-α, which indicates a greater effectiveness of the selected combination of active substances, because, unlike the single-component gel Amelotex®, the compositions developed by us additionally included a purine derivative and an immunomodulator M. The data obtained are important from the point of view of understanding the mechanism of action of a soft dosage form.Conclusion. Based on the results of previous and present studies, it is assumed that the combined composition of the soft dosage form with a half (0.5 %) concentration of meloxicam is of greatest interest for clinical practice, since its use at a high level of effectiveness additionally reduces the likelihood of adverse reactions from the non-steroidal anti-inflammatory drug, which is important in the case of long-term therapy of osteoarthritis.

Introduction. In modern pharmacology, more and more widely used molecular complexes (MC) based on donor-acceptor or, on weaker, intermolecular interactions, to stabilize dosage forms in the composition of pharmaceutical substances or their targeted delivery. This trend is actively developing, because the molecules forming MK, which has a certain composition and spatial structure, are preserved and can be released unchanged. The use of MC in tandem with "classical" metal-containing coordination compounds, which enhance or modify the action of the active component, allows the development of new, more effective drugs with optimized bioavailability and activity.Aim. Evaluation of the wound-healing effect of new substances based on aqueous systems containing coordination compounds of copper(II) or zinc with MC adenosine-copolymer of N-vinylpyrrolidone, in comparison with the drug Depantol® on a model of thermal burn in mice.Materials and methods. Mononuclear alainate complexes Cu(Ala)2 · H2O and Zn(Ala)2 (Ala – alainate-anion), copolymer of N-vinylpyrrolidone with crotonic acid (PVP-CA) have been synthesized. The composition of the obtained compounds was confirmed by the data of elemental analysis on a CHN (S) analyzer LECO CHNS (O) 932 (Elemental Microanalysis Ltd, Great Britain). IR spectra of the samples were recorded on a IRAffinity-1 (Shimadzu, Japan) instrument (by tabletting a sample with KBr) and a IRTracer-100 (Shimadzu, Japan) instrument equipped with a Specac Quest ATR attachment (Shimadzu Corporation, Japan). Potentiometric titration of the functional groups of the VP copolymer was performed using a PP-20 pH meter (Sartorius AG, Germany). The solutions of the preparations were prepared by dissolving PVP-KK in polyethylene glycol (PEG-400), followed by the addition of an aqueous dispersion of adenosine (Ad) and the corresponding complex of copper(II) or zinc into the preparation. After modeling a thermal burn of the third degree, the overall mortality in the groups and the dynamics of healing of the injured area were assessed. During the experiment, histological studies of areas of damaged tissue after staining of preparations with hematoxylin and eosin were carried out and a generalized scoring assessment of the characteristics of the burn process was carried out, including an assessment of the width and depth of the formed scar tissue, the severity of inflammatory infiltration and the presence of hemosiderosis in the tissues.Results and discussion. The formation of the MC of the copolymer of N-vinylpyrrolidone with crotonic acid with adenosine made it possible to prepare solutions of preparations containing up to 5 % (wght.) Of the latter. In the obtained samples, the molar ratio of PVP-CA : Ad : M(Ala)2 was 100 : 10 : 1 (M = CuII, Zn), the pH level of the obtained preparations was 7.0–7.1. The resulting funds were applied to the damaged area of the skin in a volume of 0.1 ml/day, each individual, daily for 4 weeks. Introductory substances based on MC PVP-CA : Ad : M(Ala)2 showed a moderate wound healing effect in comparison with the drug Depantol®, based on a water-fat emulsion. Substances that do not contain a metal complex and contain Cu(Ala)2 showed better efficiency in the dynamics of healing a burn injury in comparison with other studied substances, which was combined with a low mortality rate of experimental animals in these groups (3 cases and 2 cases out of 9 individuals, respectively). The reference drug – Depantol®, in turn, showed the best result, probably due to the content in its composition, in addition to dexpanthenol, which is characterized by a wound-healing effect, chlorhexidine antiseptic, and a fatty base, which reduces the dehydration of the injured area.Conclusion. Experimental substances based on aqueous solutions of adenosine-polymer MK showed a moderate wound healing effect comparable to the reference drug, which, however, is of sufficient interest for further study of such compositions, or their modified versions with the addition of antimicrobial components on thermal burn models, in order to creation of new, more effective drugs for the healing of wound surfaces.

Introduction. For the treatment of non-alcoholic fatty liver disease (NAFLD), hepatoprotective drugs are actively used. The existing models of non-alcoholic fatty liver disease used to study the effectiveness of medicinal products are characterized by a long duration of recovery and high mortality of test systems, in connection with which, the actual task is to test the screening model of this pathology. A number of studies have shown the hepatotoxic activity of orotic acid (OK), species-specific for rats, leading to the development of NAFLD. Aim. Approbation of the NAFLD model induced by orotic acid on 2 rodent species (mice and rats), research of the reversibility of pathology under the action of a reference drug (ursodeoxycholic acid – UDCA). Materials and methods. The reseacrh was conducted on outbred male rats weighing 260–265 g ( n = 21) and inbred male mice of the C57BL/6 line weighing 16–18 g ( n = 30). By randomization, the rats were divided into 3 groups (7 rats each): group 1 – intact animals; group 2 – NAFLD model; group 3 – NAFLD + UDCA model, mice were divided into 2 groups (10 and 20 mice, respectively): group 1 – intact animals; group 2 – NAFLD model. NAFLD was modeled by a high-carbohydrate diet with orotic acid (75 % standard feed, 24 % fructose and 1 % potassium orotate). UDCA was administered after the first control point 1 time a day through a probe in terms of 150 mg/kg. Biochemical and histological examination was carried out. Results and discussion. It was revealed that a high-carbohydrate diet with the addition of 1 % potassium orotate for 4 weeks causes moderate balloon dystrophy, mild hepatitis and an increase in the content of alanine aminotransferase and aspartate aminotransferase in the blood of rats and less significant changes in mice. Low animal mortality was also noted. The use of UDCA on the claimed model causes a decrease in the severity of liver dystrophy and a decrease in the level of liver enzymes in the blood. Conclusion. Based on the conducted experiments, rats turned out to be the optimal test system on the reproduced model, and a high-fat diet with the addition of orotic acid allows screening studies of drugs with hepatotropic activity.

Introduction. Osteoarthritis (OA) is the most common joint disease that affects more than 10 % of the world's population. More than 600 000 people are diagnosed for the first time each year, but these data do not reflect the true prevalence of the disease, since not all patients seek help from hospitals [1, 2].Aim. Pharmaceutical development of the composition and technology of a gel based on meloxicam, a purine derivative and an immunomodulating component for the treatment of OA with pharmacological substantiation of the content of active substances.Materials and methods. A combination of three active pharmaceutical substances was studied: a non-steroidal anti-inflammatory drug – meloxicam, a purine derivative and an original immunomodulator M. Sodium alginate, natrozole and xanthan gum were considered as gelling agents. Were identified two technological modes of obtaining a gel base. The concentrations of active substances were selected based on the results of preclinical studies. OA was modeled by the combined administration of 0.1 ml of a mixture of Freund's complete adjuvant with a 10 % talc suspension in isotonic sodium chloride solution in a ratio of 1 : 10 into the hock (tarsus) joint cavity. The criteria for choosing the optimal composition of the gel were the size of the damaged joint, exercise tolerance and the histological picture in comparison with intact and control animals. For quantitative data, sample mean values (M) and standard deviations (SD) were calculated. The results corresponded to the laws of normal distribution, statistical processing was carried out using one-way analysis of variance (One-Way ANOVA) using the GraphPad Prism 8.0.2 software, USA at the level of statistical significance of differences p < 0,05 и p < 0,001.Results and discussion. The composition was developed and the technology of the topical dosage form based on sodium alginate was proposed. Preclinical data indicate that the highest efficacy is achieved when using a formulation containing 3 % purine derivative, 5 % immunomodulator M and 0.5 % meloxicam. The developed composition for the effectiveness of suppressing the symptoms of OA showed results that exceeded the reference drug.Conclusion. An original combined agent for the treatment of OA has been developed. Due to the selected component composition, with greater efficiency, it was possible to reduce the dosage of meloxicam to 0.5 %, and the use of sodium alginate as a gelling agent contributed to the prolongation of the action of the gel and the subsequent reduction in the number of applications.

Introduction. Cytochrome C is a metabolic drug that has an antihypoxic, trophic effect, stimulates regeneration processes, and is also used in various eye diseases.Aim. The task of the work was to determine the specific activity of cytochrome C eye drops in comparison with emoxipin.Materials and methods. As a test system, Soviet chinchilla male rabbits were used, the simulation of traumatic erosion and acid burn was carried out, followed by the use of test eye drops. In forming erosion, the method of C. Hanna, J. E. O'Brien (1960) with scraping of the corneal epithelium, an acid burn in the experiment was formed under local anesthesia (0.4% inocain) application of filter paper (in the form of a circle with a diameter of 8 mm) moistened with 3% acetic acid solution with an exposure of 5 seconds on the cornea. The effectiveness evaluation was carried out on the basis of a scale proposed by the authors, which allows histologically to take into account corneal changes during the pathological process. Descriptive statistics methods were used for all quantitative data: the average sample values (M) and standard deviations (SD) were calculated. The distribution in each data sample was analyzed using the Shapiro – Wilk criterion. Under normal distribution, analysis of variance was used followed by a posteriori analysis (Tukey criterion). If the data had an abnormal distribution, the Kruskal-Wallis test was calculated.Results and discussion. The integrity of the patterns of traumatic erosion and acid burn was histologically confirmed. The therapeutic efficacy of eye drops of emoxipin in the full dose was not sufficiently pronounced and comparable to that of cytochrome C in half the therapeutic dose. Cytochrome C in therapeutic and dual therapeutic dose effectively coped with the effects of acid burn and traumatic erosion when used in the form of eye drops for 28 days.Conclusion. Cytochrome C eye drops, used at a therapeutic dose and a dose exceeding the therapeutic dose 2 times, have a pronounced regenerative effect in traumatic erosion and acid burn of the rabbit eye cornea. The effect of Cytochrome C eye drops at half the therapeutic dose, as well as the reference drug (emoxipin) at the therapeutic dose, is not very pronounced.

Introduction. Hypertension is the most common non-infectious disease in the world. New clinical recommendations for the diagnosis and management of patients with arterial hypertension are considering the issue of prescribing combination therapy and prefer fixed combinations of drugs in a single pill. The study of the pharmacokinetics of medicinal substances and the consideration of their pharmacokinetic parameters today is a necessary step in the complex of work, both in the creation of new original medicines and in the application of known generic drugs, and this is primarily due to obtaining objective characteristics of all processes occur in the body of the animal (human) with the drug. Pharmacokinetics is assessed in individual studies or as part of efficacy, safety, and tolerability studies.Aim. The study of the release of lercanidipine from bilayer tablets containing two API (ramipril and lercanidipine) in the dissolution medium used for quality control in vitro and release in vivo, after oral administration of the drug to rabbits.Materials and methods. Studies have been conducted on the release of lercanidipine from the combined drug in vitro and in vivo. As a test system were used laboratory rabbits Soviet chinchilla breed. Pharmacokinetic parameters were determined.Results and discussion. A graph of the release of lercanidipine from the combined drug was constructed and the dependence of the concentration of this substance in the blood plasma of rabbits on time was revealed. Calculated pharmacokinetic parameters. An in vivo release study shows that the pharmacokinetics of lercanidipine are consistent with literature data.Conclusion. The test drug has all the advantages of a rational fixed combination of antihypertensive drugs and simplifies therapy, meets the requirements of the latest clinical guidelines.