Single Intragastric Administration Research Articles

Pharmacokinetics of Enrofloxacin in Plasma, Urine, and Feces of Donkey (Equus asinus) after a Single Intragastric Administration.

Enrofloxacin is a broad-spectrum antimicrobial agent, but the study of its pharmacokinetics/pharmacodynamics (PKs/PDs) in donkeys is rarely reported. The present study aimed to investigate the pharmacokinetics of enrofloxacin administered intragastrically, and to study the pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in plasma, urine, and feces, and the PK/PD parameters were investigated to provide a rationale for enrofloxacin treatment in donkeys. A total of five healthy donkeys were selected for intragastric administration of 7.5 mg·kg-1 BW of enrofloxacin by gavage, and blood, urine, and fecal samples were collected. The results showed that the elimination half-life of plasma enrofloxacin was 11.40 ± 6.40 h, Tmax was 0.55 ± 0.12 h, Cmax was 2.46 ± 0.14 mg·L-1, AUC0-∞ was 10.30 ± 3.37 mg·L-1·h, and mean residence time (MRT) was 7.88 ± 1.26 h. The Tmax of plasma ciprofloxacin was 0.52 ± 0.08 h, Cmax was 0.14 ± 0.03 mg·L-1, and AUC0-∞ was 0.24 ± 0.16 mg·L-1·h. Urinary Cmax was 38.18 ± 8.56 mg·L-1 for enrofloxacin and 15.94 ± 4.15 mg·L-1 for ciprofloxacin. The total enrofloxacin and ciprofloxacin recovered amount in urine was 7.09 ± 2.55% of the dose for 144 h after dosing. The total enrofloxacin and ciprofloxacin recovered amount in feces was 25.73 ± 10.34% of the dose for 144 h after dosing. PK/PD parameters were also examined in this study, based on published MICs. In conclusion, 7.5 mg/kg BW of enrofloxacin administered intragastrically to donkeys was rapidly absorbed, widely distributed, and slowly eliminated in their bodies, and was predicted to be effective against bacteria with MICs < 0.25 mg·L-1.

Pharmacokinetics of tilmicosin in plasma, urine and feces after a single intragastric administration in donkey (Equus asinus).

Tilmicosin, a macrolide antibiotic, has the potential to treat bacterial infections in donkeys. However, the pharmacokinetics of tilmicosin in donkeys have not been reported. The aim of this study was to investigate the pharmacokinetics of tilmicosin in donkey plasma, urine, and feces after a single intragastric administration to determine the suitability of tilmicosin for donkeys. A total of 5 healthy male donkeys with similar body weights were selected. The donkeys were administered a single dose of 10 mg · kg-1 body weight (BW) tilmicosin by gavage. The concentrations of tilmicosin in plasma, urine, and feces were determined. The results showed that after a single intragastric administration of 10 mg · kg-1 body weight, tilmicosin in donkey plasma reached a maximum concentration of 11.23 ± 5.37 mg · L-1 at 0.80 ± 0.10 h, with a half-life of 14.49 ± 7.13 h, a mean residence time of 28.05 ± 3.05 h, a Cl/F of 0.48 ± 0.18 L · kg-1 · h-1, and a Vd/F of 9.28 ± 2.63 Lkg-1. The percentage of tilmicosin excreted through the urine of donkeys is 2.47%, and the percentage excreted through the feces is 66.43%. Our study provides data to inform the use of tilmicosin in donkeys.

Comparison of in vivo pharmacokinetics of twelve constituents in Qihe Fenqing Yin in normal rats and diabetic rats

This paper aims to study the pharmacokinetic differences of twelve effective constituents(succinic acid, neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, protocatechuic aldehyde, caffeic acid, 5-O-ferulogeninic acid, p-coumaric acid, nuciferine, quercetin, oleanolic acid, and ursolic acid) in Qihe Fenqing Yin in normal and diabetic rats. The diabetic rat model was established by a high-fat diet combined with intraperitoneal injection of streptozocin. A UHPLC-QTRAP-MS/MS method was established for the simultaneous determination of 12 constituents in the plasma of normal rats and model rats after a single intragastric administration of Qihe Fenqing Yin. The results show that the established analytical method has a good linear relationship with the 12 components, and the specificity, accuracy, precision, and stability meet the requirements. The computational pharmacokinetic parameters are fitted by DAS 3.2.8 software, and the results show that the half-life time(t_(1/2)) of the other nine components in the model group was longer than that in the normal group except for caffeic acid, 5-O-ferulogeninic acid, and oleanolic acid. The area under curve(AUC_(0-t)) of cryptochlorogenic acid, p-coumaric acid, ursolic acid, and oleanolic acid increases compared with the normal group. Meanwhile, mean residence time(MRT) delays. The &quot;double peaks&quot; of quercetin and nuciferine in the normal group are not observed in the model group, suggesting that the pharmacokinetic parameters of the drugs in the disease state are significantly different.

Influence of new dimethylaminoethanol derivatives, butanoic and trans-butenedioic acids, on the tolerability of hypoxia, hyperthermia, and hypothermia

BACKGROUND: The need to increase the tolerance of various extreme effects is associated not only with the expansion of human professional activity regions but also with the need to assist victims of natural and man-made disasters. The use of pharmacological agents for individual adverse effects is a well-known method; however, considering the combined effects of several physical or chemical factors, only a few references are found in the literature.&#x0D; AIM: This preclinical study aimed to examine the effectiveness of a new derivative of aminoethanol and intermediates of the Krebs cycle in relation to the isolated and combined effects of hypoxia and temperature (hyperthermia and hypothermia).&#x0D; MATERIALS AND METHODS: The fumaric salt of the amber ether of diethylaminoethanol was synthesized at St. Petersburg State University of Chemistry and Pharmacy, Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was conducted on small laboratory animals. Resistance to hypoxia was assessed by the dynamics of the altitude threshold of animals, tolerance to hyperthermia by survival in a thermal chamber at 40°C, and tolerance to hypothermia by the time of maximum swimming in water at 10–12°C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was induced by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, and thermal exposure was induced by placing the animal in water at 40°C (hyperthermia) or 9–11°C (hypothermia).&#x0D; RESULTS: After a single intragastric administration in a wide range of doses, the test compound stimulated the physical performance of animals and exhibited a protective effect under the isolated effects of hypobaric hypoxia, hyperthermia, and hypothermia. With combined exposure to hemic hypoxia and hyperthermia, the compound was effective at a dose of 250 mg/kg. With combined exposure to hemic hypoxia and hypothermia, efficiency was also noted at lower doses (25 and 50 mg/kg).&#x0D; CONCLUSION: Fumaric salt of dimethylaminoethanol amber ether, a new derivative of dimethylaminoethanol, butenedioic, and trans-butenedioic acids, is promising for further study as a means of increasing the body’s resistance to extreme influences.

Optimization of algorithms for in vivo preclinical screening of compounds with an alleged antitumor effect

BACKGROUND: Despite a large number of publications on preclinical studies of compounds with a suspected antitumor effect on in silico and in vitro models, in vivo studies are the most informative. The experimental part of the work on laboratory animals has its own peculiarities in the field of preclinical research: a large number of animals and analog compounds in the series, two- and three-phase staging, and, consequently, high cost and labor-intensive execution.&#x0D; AIM: Optimization of algorithms for screening preclinical in vivo studies of compounds with a suspected antitumor effect.&#x0D; MATERIALS AND METHODS: To form the algorithm in the preclinical study, primary data was obtained using standard pharmacological (determination of the toxicity class index, antitumor and antimetastatic activity, inhibition of tumor growth by weight, average life expectancy of animals) and morphological (autopsy, micropreparations with hematoxylin and eosin staining, as well as immunohistochemical study using monoclonal antibodies) methods with the selection of leading compounds for in-depth study with a description of the mechanism of pharmacological activity.&#x0D; RESULTS: Based on a series of comparative experiments, the following algorithm of preclinical in vivo study for newly synthesized compounds with an alleged antitumor effect has been tested.&#x0D; Stage 1. Determination of the toxicity class with a single intragastric administration to Wistar rats according to the Organization for Economic Co-operation and Development 420 protocol and selection of candidates for antitumor drugs according to the principle of the greatest safety of use.&#x0D; Stage 2. Determination of the presence/absence of pharmacological activity of the tested compounds. Compounds of toxicity classes IV and V (according to the Globally Harmonized System of Hazard Classification and Labeling of Chemical Products) in a wide range of doses (doses are selected depending on the toxicity class) are examined for pharmacological activity before the natural death of tumor-bearing animals with the identification of leader substances, in-depth study of which is appropriate. The selection of promising substances and total doses for administration at the next stage is determined by the life expectancy of tumor-bearing animals.&#x0D; Stage 3. Determination of indicators of antitumor and antimetastatic activity of leader substances with a fixed euthanasia period for all tumor-bearing animals and determination of possible mechanisms for the implementation of the therapeutic effect using immunohistochemical analysis.&#x0D; Stage 4. To study the effect of the tested compounds on the growth rates of the primary tumor node and metastatic foci at different stages of the development of the tumor process, when administered in different modes, as part of combined and monochemotherapy, with mandatory clarification of the mechanisms for the implementation of antitumor and antimetastatic activity using biochemical and immunohistochemical techniques.&#x0D; Stage 5. The study of the most promising compounds according to the guidelines for preclinical safety studies for the purpose of clinical trials and registration of medicines (the document was approved by the decision of the Board of the Eurasian Economic Commission of November 26, 2019, N 202): «Toxicity studies with repeated (multiple) administration of the drug, preclinical studies conducted in order to justify the conduct of exploratory clinical studies, studies of local tolerability of the drug, studies of genotoxicity of the drug, carcinogenicity of the drug, etc.»&#x0D; CONCLUSIONS: The step-by-step exclusion of the tested compounds from the line of similarly-structured substances described by us will increase the efficiency of selecting promising candidates for antitumor drugs and reduce the cost of conducting preclinical studies of compounds with an alleged antitumor effect.

Acute toxicity of zinc carbonate nanocrystals on white mice model

Zinc-based nanoparticles (NPs) are successfully used to meet the mineral needs of animals and poultry, capable of increasing the growth rate and the efficiency of their use of feed. Nanoparticles of zinc oxide are widely used, which are superior to conventional sources of zinc in terms of pharmacological activity and bioavailability, have a positive effect on productivity and antioxidant protection, and increase reproductive potential. However, a detailed investigation of their toxicological parameters showed the risks of their introduction into the body, as a result of which a large number of zinc oxide NPs were synthesized by the methods of “green chemistry”, the main drawback of which is a complex methodology and a high level of costs. We investigated the acute toxicity of a colloidal solution of zinc carbonate nanocrystals in a model of white mice. The experiment was conducted on 42 female non-linear white mice, 3–4 months old, with a live weight of 21–23 g, kept under optimal vivarium conditions. According to the principle of analogues, 6 experimental groups were formed: mice were injected with a colloidal solution of zinc carbonate nanoparticles in doses (by absolute weight of the drug) of 15,000.0; 20000.0; 25000.0; 30000; 35000.0 and 40000.0 mg/kg of body weight based on the absolute weight of the drug, which according to the active substance (zinc carbonate nanoparticles) was (37.5; 50.0; 62.5; 75.0; 87.5 and 100, 0 mg/kg of body weight), orally using an esophageal-gastric tube. Mice of the control group were injected with distilled water in a volume of 0.2 cm3 according to the same protocol. The clinical condition of the experimental animals was observed for 14 days, noting the appearance and development of clinical signs of poisoning, the time of death or recovery to the physiological norm. After the death (diagnostic slaughter) of the animals, a pathological autopsy was performed. Clinical observations showed that a single intragastric administration of the drug to mice of experimental groups 1-6 did not cause acute poisoning. The deaths of mice in all experimental groups were not observed during the 14-day observation period, as a result of which the LD50 indicator could not be calculated. At the same time, the maximum possible injected dose of the colloidal solution of zinc carbonate nanoparticles (by absolute weight) was 40,000.0 mg/kg of body weight (100.0 mg/kg by active substance), which allows the drug to be assigned to the VI class of toxicity – substances are relatively harmless (LD50 &gt; 15000.0 mg/kg of body weight), and according to the degree of danger up to IV class – low-hazardous substances (LD50 &gt; 5000.0 mg/kg of body weight).

Study of acute toxicity of a new drug “AOS” for the treatment of osteoporosis.

Background. Osteoporosis is one of the most common diseases, which, along with myocardial infarction, stroke, cancer, and sudden death, occupies a leading place in the structure of morbidity and mortality of the population. Postmenopausal women are most vulnerable and are approximately 4 times more likely to be affected than men (80 % of all patients), and osteoporosis-related fractures are responsible for a significant increase in morbidity, disability, and mortality, especially in the elderly.Objective. To study the acute toxicity of the new drug “Antiosteoporosis drug” (patent No. 02-04-16643/15-0 dated February 26, 2015) with a single intragastric administration to mature outbred rats of both sexes.Design and methods. The study was conducted on outbred rats of both sexes according to protocol OECD 420, GOST 32296-2013. The development of a toxic effect was concluded based on behavioral tests, clinical examinations, changes in body weight, the results of pathomorphological examination of organ tissue and biochemical parameters of blood and urine.Results. According to the results of the study, the tested drug was classified according to the active substance into category 5 according to the GHS classification (2000&lt;LD50 (i/g)&lt;5000 mg/kg). An assessment of the dynamics of body weight in experimental animals showed that a single intragastric administration of the test drug had no effect on this indicator. The study of individual behavior as part of the main study on the 14th day after a single intragastric administration of the test drug showed that a single intragastric administration of the test drug at a dose of 2000 mg/kg did not have a delayed effect on the general condition and indicative research activity of experimental animals. Autopsy and pathological examination of animals on the 15th day after a single intragastric administration of the test drug did not reveal the presence of any residual effects associated with the administration of the test drug. The tested drug did not have a local irritant effect on the injection site — the gastrointestinal tract. In all tests, the degree of change in indicators caused by the test drug was the same: there were no statistically significant differences in the recorded parameters between the test drug and the control group.

Experimental Evaluation of the Pharmacological Safety of a New Propagandic Acid Derivative with a Cardiotropic Action

We present the results of experimental studies into the pharmacological safety of a pharmaceutical substance 4-[(3-oxo-3-ethoxypropanoyl)amino]benzoic acid (Etmaben) under a single intragastric administration at various experimental doses (60–3000 mg/kg) to female laboratory outbred rats. A clinical examination of the experimental animals was carried out in order to identify signs of intoxication. To that end, the level of food and water consumption was assessed and biochemical blood tests were performed. In addition, the state of the central nervous and cardiovascular systems, physical endurance, and respiratory rate were assessed. The tested pharmaceutical substance in the studied doses after a single intragastric administration to female rats had no negative effect on the behavior, blood parameters, the state of the central nervous system and the cardiovascular system of experimental animals.

Влияние гепатопротекторного фитокомплекса на выраженность эндогенной интоксикации у лабораторных крыс при экспериментальной патологии печени, вызванной гидразином

Abstract. The purpose is to study the influence of the hepatoprotective phytocomplex on the severity of endogenous intoxication in laboratory rats with experimental liver pathology caused by hydrazine. Methods. The studies were carried out on non-linear rats, formed into 3 groups (n = 10). Toxic damage to the liver in rats of groups 1 and 2 was modeled by a single intragastric administration of hydrazine at a dose of 200 mg/kg of body weight. Immediately after intoxication and for the next three weeks in 1st group, the drug fitosomin was used – daily orally in the form of boluses at a dose of 0.5 g/kg of body weight, 2nd group after intoxication received empty cereal boluses, 3rd group was intact. In dynamics, the degree of endogenous intoxication was studied by the concentration of medium mass molecules (MMM) in the blood of animals at λ = 254 and 280 nm. Scientific novelty. Experimentally new data on the pharmacological effects of the hepatoprotective phytocomplex was obtained, which includes lecithin, dihydroquercetin, extracts of milk thistle, agrimony and golden boletus. For the first time, the effectiveness of the drug fitosomin was determined to reduce the severity of the endogenous intoxication syndrome in laboratory rats with experimental liver pathology caused by hydrazine. Results. It has been determined that hydrazine-induced liver pathology in laboratory rats is accompanied by the development of endogenous intoxication syndrome with a more pronounced increase in the blood fraction of MMM 254 relative to MMM 280. The use of fitosomin leads to a weakening of the toxic effect of hydrazine both on the liver and on the body of animals as a whole. The course application of the hepatoprotective phytocomplex increases the survival rate of rats, improves their clinical condition and leads to a decrease in the concentration of MMM in the blood. The obtained results outlined the prospects for the use of the drug fitosomin in veterinary practice in case of liver damage, as well as intoxication of animals.

New synthetic monophenolic antioxidant TS-13 penetrates the blood-brain barrier

TS-13 (sodium 3-(3’-tert-butyl-4’-hydroxyphenyl)propylthiosulfonate) is a synthetic antioxidant that has demonstrated biological effectiveness in numerous studies in modeling pathological conditions in vivo, in particular, in the model of Parkinson’s disease. In order to establish whether these effects are mediated or associated, among other things, with the direct effect of TS-13 on the organs and tissues of animals, in this work, the concentration of TS-13 in rat blood plasma and brain after intragastric administration was determined. Material and methods. After a single intragastric administration of a solution of TS-13 at a dose of 100 mg/kg, biomaterial (blood, brain) was taken for 24 h in male Sprague Dawley stock rats (n = 57). To measure the concentration of a substance in samples, a bioanalytical method was developed and validated using high-performance liquid chromatography with UV detection. Results and discussion. The method of quantitative determination was developed by us for the first time and validated before the study. It has been established that the calculated values of the calibration samples meet the acceptance criteria (have the required accuracy and precision) in the concentration range from 0.05 to 6 µg/ml, R=0.9998. The results of determining TS-13 concentration in rat blood plasma and brain showed that after a single administration per os, the compound enters the blood, where it is detected for 15 h (mean retention time 7.94 h, half-life 7.59 h, elimination constant 0.13 h-1, total clearance 40.1 l/(kg × h)), and also penetrates the blood-brain barrier, quickly entering the brain (maximum concentration is reached after 1 h). The compound has a low affinity for brain tissue (tissue availability 0.32), and therefore its concentration does not reach high values, however, a slow excretion of the substance is observed - the average retention time is 6.56 h, the half-life is 6.43 h, the elimination constant 0.11 h-1. Conclusions. After a single intragastric administration to rats, TS-13 enters the blood, where at least part of it is detected unchanged after 30 minutes, reaching maximum values after 1 hour. Similar kinetics of the substance is characteristic of the brain, where it is found in smaller amounts. Thus, as a result of the study, it was shown that TS-13 penetrates the blood-brain barrier and is able to directly affect brain structures, which, however, does not negate the possibility of an indirect effect mediated by the ability to change the activity of intra- and intercellular signaling systems.

Experimental evaluation of the acute toxicity and irritant effect of “BTF plus” – a veterinary medicinal product for the normalization of metabolic processes in animals and poultry

Laboratory studies were conducted to determine the acute toxicity of the veterinary drug “BTF plus” on white rats and white mice. The preparation “BTF plus” is a complex vitamin and mineral preparation, which is used to normalize and correct metabolic processes in poultry and animals. The drug is used for various types of animals and poultry as a stimulating, tonic and general strengthening agent for: obstetric pathologies (difficult births, postpartum complications, paresis, eclampsia, sexual cycle disorders); metabolic disorders caused by irrational feeding, malnutrition, asthenic syndrome, etc.; anemia with helminthiasis; secondary anemias, as an additional means in the treatment of magnesium and calcium deficiency; to increase muscle activity, with significant loads, overstrain and exhaustion in animals; to increase the body’s resistance to various pathogens; to stimulate growth, development and live weight gain in young animals; as an additional means in the treatment of diseases caused by various factors (infectious and non-infectious origin). Based on the results of determining the parameters of the acute toxicity of the drug “BTF plus” in the case of a single intragastric administration to white female rats, it was not possible to calculate the LD50, since the death of laboratory animals was not detected within 14 days after administration. At the same time, the maximum injected dose (based on the absolute weight of the drug) was 40000.0 mg/kg of body weight, which allows the drug to be classified as VI class of toxicity – the substances are relatively harmless (LD50 &gt; 15000.0 mg/kg of body weight), and according to the degree of danger to IV class – low-hazardous substances (LD50 &gt; 5000.0 mg/kg of body weight). Based on the results of determining the parameters of the acute toxicity of the drug “BTF plus” in the case of a single subcutaneous injection to white female rats and male mice, it was not possible to calculate the LD50, since the death of laboratory animals was not detected within 14 days after administration. At the same time, the maximum injected dose (based on the absolute weight of the drug) was 20000,0 and 40000.0 mg/kg of body weight for both species of animals, respectively, which allows it to be classified as VI class – relatively harmless substances (LD50Subcut &gt; 4500 mg/kg of body weight). Further studies will be the next stage of pre-registration tests aimed at studying the embryotoxic effect of “BTF plus”, which is mandatory material of the “Safety and residue studies” section of the dossier for this drug.

Toxicological studies of additives feed endoforce multi on laboratory animals

The creation of new drugs and feed additives is an urgent task that contributes to the growth of the efficiency of the livestock and poultry industries of agriculture, especially during the period of import substitution in the Russian Federation. An experimental study of possible changes in the body of laboratory animals after single or multiple uses of new feed additives is necessary for the toxicological assessment of newly created products. Single intragastric administration of feed additive Endoforce Multi containing live vegetative cells and spores of cultures: Bacillus subtilis B-5449, Bacillus subtilis B-1323, Bacillus subtilis B-3679 - 5.0 109 CFU / ml, at a dose many times higher than recommended, did not lead to the death of laboratory animals, which confirmed the absence of its acute toxicity. Over the entire observation period, the authors did not note any disturbances in the rats’ behavioural reactions and physiological states. Determination of chronic toxicity was carried out for 30 days. The studied suspension of the feed additive was given with water to rats of the experimental groups at doses: 1st - 100 mg, 2nd - 150 mg and 3rd - 200 mg per head. At the end of the empirical study, an increase in the number of erythrocytes by 2.68–3.72 1012/l, haemoglobin - by 41.50–61.58 g/l in laboratory animals of the experimental groups compared with the control ones was revealed, which indicated an increase in blood oxygenation and the organism as a whole. In addition, in the rats of the experimental groups, a decrease in the content of urea in the blood to 3.14 ± 0.53 - 4.68 ± 0.41 mmol / l and creatinine to 32.26 ± 5.18 - 48.13 ± 6.23 µmol/l. The opposite trend was observed when determining the serum activity of alkaline phosphatase, which increased by 39.0–52.6% in intact individuals, which indicated dynamic processes of growth, formation and development of the skeleton. According to the results of the autopsy of the rats of the studied groups, regardless of the dose of the introduction of the feed additive Endoforce Multi, no pathological changes in the colour, consistency and size of the internal organs were registered.

Ecological and toxicological assessment of hazard of contamination of water bodies by the γ-polyoxymethylene

Introduction. In the process of production, storage and application of the representative of new components of solid rocket fuels – γ-polyoxymethylene, its ingress into the water of reservoirs is not excluded, which determines the mandatory assessment of the danger of its single contamination of this ecosystem.&#x0D; Material and methods. As an object of research, γ-polyoxymethylene (γ-POM, polyformaldehyde, acetal copolymer) was used – a mixture of dimethyl esters of polyoxymethylene glycols – a fine amorphous white powder, CAS registration number 66455-31-0. The empirical formula is CH3O(CH2O)nCH3 at n = 100–300. It is practically insoluble in water.&#x0D; Results. It was found that the ecotoxicant content in water at a concentration of 50.0 mg/l led to a change in its transparency. The indicated concentration of γ-POM was determined as a threshold for organoleptic harmfulness.&#x0D; In the course of studying the effect of the toxicant on the general sanitary regime of reservoirs, in the absence of changes in the indicators of biochemical oxygen consumption, its negative impact on nitrification processes and saprophytic microflora was revealed. The threshold concentration of the substance according to the general sanitary indicator of harmfulness is 3.5 mg/l.&#x0D; In experiments on laboratory animals, it was noted that a single intragastric administration of the tested xenobiotic in the form of a suspension in a 2.5% solution of aqueous starch caused a significant decrease in heart rate and a change in a number of hematological parameters. The threshold of a single general toxic effect of γ-POM is 90.0 mg/kg.&#x0D; Limitations of the study. The revealed features of the behavior of γ-polyoxymethylene must be taken into account when it once pollutes the water of reservoirs (in case of an emergency). However, the data obtained are insufficient to substantiate the hygienic standard of the connection in the water of water bodies.&#x0D; Conclusion. The results of the performed experiments indicate that a single ingress of γ-polyoxymethylene into the water represents an ecological and toxicological hazard registered for all three basic signs of harmfulness, which is taken into account when justifying its maximum permissible concentration in the water of reservoirs.

Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [3H]Catalpol in Rats: the Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke.

Catalpol, one of the main bioactive components isolated from Rehmannia glutinosa, was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate. This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [3H]catalpol in rats. Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q-Exactive plus MS. The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median Tmax of 0.75 h and an arithmetic mean half-life (t1/2) of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drugrelated substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [3H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems. Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.

Effect of mesenchymal stem cell transplantation on the structural and functional parameters of the liver in acute toxic hepatitis in rats

Acute toxic hepatitis is a serious health problem for the working population. The currently widely used pharmacological preparations with claimed hepatoprotective properties for the treatment of liver diseases have dubious therapeutic efficacy and cannot restore functional and structural changes in the damaged organ. Thus, the search for new methods of treating liver diseases, including toxic etiology, is an urgent task. An experimental study was conducted on 134 nonlinear white outbred rats (35 months) weighing 250390 g. The animals were divided into four groups: group I, control group (n = 15); group II, single intragastric administration of an oil solution of carbon tetrachloride at a dose of 1500 mg/kg (n = 41); group III, single intravenous administration of multipotent mesenchymal stem cells of the mouse (n = 20); group IV, single intragastric administration of an oil solution of carbon tetrachloride at a dose of 1500 mg/kg and subsequent intravenous transplantation of multipotent mesenchymal stem cells of the mouse (2 106) (n = 58). On days 1, 3, 5, and 7 of the experiment, blood sampling was performed for biochemical analysis, and organs and tissues were selected for histological and morphometric studies. The transplantation of multipotent mouse mesenchymal stem cells reduced the mortality of animals after exposure to carbon tetrachloride and did not cause acute toxicity. According to a morphometric study, starting from day 3, the introduction of multipotent mouse mesenchymal stem cells led to a statistically significant decrease in the infiltrative processes in the liver tissue. Statistically significant changes in the biochemical composition of the rat blood serum were noted against the transplantation of multipotent mouse mesenchymal stem cells: a decrease in the activities of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma-glutamyltransferase, amylase, creatinine, uric acid, direct and total bilirubin, and cholesterol. The transplantation of multipotent mouse mesenchymal stem cells was found to be an effective method of treating acute toxic hepatitis. The use of multipotent mouse mesenchymal stem cells contributed to an increase in the survival rate of laboratory animals and faster recovery of structural and functional disorders in liver tissue after its acute toxic damage.

Comparative analysis of morphological and biochemical changes after a single intragastric administration of hybrid organotin compounds

Introduction. Organotin compounds are promising candidates for antitumor drugs. Identification of pathogenetic features of the general toxic effect of hybrid organotin compounds during the period of the greatest severity of the intoxication clinical picture will allow to estimate the risk of hepatotoxic and nephrotoxic complications with the administration of bis (3,5–di– tert–butyl–4–hydroxyphenylthiolate) dimethyltin (Me-3) and ((3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenyltin (M-e5) as chemotherapeutic agents.Аim: To conduct a comparative analysis of morphological and biochemical changes with a single intragastric administration of hybrid organotin compounds Me-3 and Me-5 in the maximum tolerated dose (MTD) on the 7th day of the toxic process development.Material and Methods. Hybrid organotin compounds Me-3 and Me-5 were administered once intragastrically to Wistar rats (females) at a MTD of 2000 mg/kg and 750 mg/kg, respectively. Biochemical and morphological studies were carried out on the 7th day of the development of intoxication symptoms according to standard methods.Results. With the introduction of Me-3 and Me-5 in the liver, signs of fatty dystrophy of varying severity were revealed, with a predominant lesion of centrolobular hepatocytes, an increase in the size of portal tracts due to edema and fibrosis, and scant lymphocytic infiltration. With the introduction of Me-5, morphological changes were more severe, with the involvement of the vascular bed of the organ in the process. When the tested compounds were administered in the kidneys, the same type of damage to the glomerular apparatus and renal tubules was recorded, characteristic of toxic nephropathy. Unidirectional changes in the blood of experimental animals were revealed in the group of nonspecific biochemical markers of cytolysis: a moderate decrease in transaminase activity and an increase in the activity of creatine kinase (CC), lactate dehydrogenase (LDH) and creatinine levels. The process of formation of urea and protein synthesis was functionally preserved.Conclusion. On the 7th day of the development of intoxication with a single intragastric administration of hybrid organotin compounds Me-3 and Me-5 in the maximum tolerated doses, biochemical and morphological changes in the body of animals could be attributed to a moderate degree of severity.

Comparative analysis of morphological and biochemical changes after a single intragastric administration of hybrid organotin compounds

Introduction. Organotin compounds are promising candidates for antitumor drugs. Identification of pathogenetic features of the general toxic effect of hybrid organotin compounds during the period of the greatest severity of the intoxication clinical picture will allow to estimate the risk of hepatotoxic and nephrotoxic complications with the administration of bis (3,5–di–tert–butyl–4–hydroxyphenylthiolate) dimethyltin (Me-3) and ((3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenyltin (M-e5) as chemotherapeutic agents.The aim of the study is to conduct a comparative analysis of morphological and biochemical changes with a single intragastric administration of hybrid organotin compounds Me–3 and Me-5 in the maximum tolerated dose (MTD) on the 7th day of the toxic process development.Material and Methods. Hybrid organotin compounds Me-3 and Me-5 were administered once intragastrically to Wistar rats (females) at a MTD of 2000 mg/kg and 750 mg/kg, respectively. Biochemical and morphological studies were carried out on the 7th day of the development of intoxication symptoms according to standard methods.Results. With the introduction of Me-3 and Me-5 in the liver, signs of fatty dystrophy of varying severity were revealed, with a predominant lesion of centrolobular hepatocytes, an increase in the size of portal tracts due to edema and fibrosis, and scant lymphocytic infiltration. With the introduction of Me-5, morphological changes were more severe, with the involvement of the vascular bed of the organ in the process. When the tested compounds were administered in the kidneys, the same type of damage to the glomerular apparatus and renal tubules was recorded, characteristic of toxic nephropathy. Unidirectional changes in the blood of experimental animals were revealed in the group of nonspecific biochemical markers of cytolysis: a moderate decrease in transaminase activity and an increase in the activity of creatine kinase (CC), lactate dehydrogenase (LDH) and creatinine levels. The process of formation of urea and protein synthesis was functionally preserved.Conclusion. On the 7th day of the development of intoxication with a single intragastric administration of hybrid organotin compounds Me-3 and Me-5 in the maximum tolerated doses, biochemical and morphological changes in the body of animals could be attributed to a moderate degree of severity.

Nanoencapsulation of Vaccinium ashei Leaf Extract in Eudragit® RS100-Based Nanoparticles Increases Its In Vitro Antioxidant and In Vivo Antidepressant-like Actions.

Depression is a major psychiatric disorder in Brazil and worldwide. Vaccinium ashei (V. ashei) leaves are cultivation by-products with high bioactive compound levels. Here, a hydroalcoholic extract of V. ashei leaves (HEV) was associated with Eudragit® RS100-based nanoparticles (NPHEV) to evaluate the in vitro antioxidant and in vivo antidepressant-like effects. Interfacial deposition of the preformed polymer method was used for NPHEV production. The formulations were evaluated regarding physicochemical characteristics, antioxidant activity (DPPH radical scavenging and oxygen radical absorbance capacity), and antidepressant-like action (1-25 mg/kg, single intragastric administration) assessed in forced swimming and tail suspension tests in male Balb-C mice. The NPHEV presented sizes in the nanometric range (144-206 nm), positive zeta potential values (8-15 mV), polydispersity index below 0.2, and pH in the acid range. The phenolic compound content was near the theoretical values, although the rutin presented higher encapsulation efficiency (~95%) than the chlorogenic acid (~60%). The nanoencapsulation improved the HEV antioxidant effect and antidepressant-like action by reducing the immobility time in both behavioral tests. Hence, Eudragit® RS100 nanoparticles containing HEV were successfully obtained and are a promising alternative to manage depression.

Preclinical study of pharmacokinetic ADME processes of phenosanic acid &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt;

BACKGROUND: Phenosanic acid is a synthetic antioxidant, the active ingredient of the original domestic drug recommended for the treatment of epilepsy. To improve the effectiveness and safety of the use of phenosanoic acid, additional study of its pharmacokinetic properties is necessary.&#x0D; AIM: To study the pharmacokinetic parameters of the active ingredient of the drug Dibufelon, capsule 200 mg (LLC Piq-Pharma, Russia) in vitro and in vivo systems in rats after single administration in one dose.&#x0D; MATERIALS AND METHODS: Phenosanic acid binding to blood plasma proteins, microsomal stability and permeability through the monolayer of Caco-2 cells were evaluated in in vitro tests. The pharmacokinetics parameters were studied after a single intragastric administration in Wistar rats in dose of 80 mg/kg. The samples were analyzed by HPLC-UV.&#x0D; RESULTS: A high variability in the degree of binding of phenosanic acid to blood plasma proteins by 2065% depending on the concentration was revealed, relatively high microsomal stability (half-life 1106 789 min, internal clearance 2.05 0.86 l/min/mg protein of liver microsome; residual content after 60 min incubation 87.9 7.8%) and the ability to penetrate through the monolayer of cells Caco-2. The rapid absorbtion of the substance into the systemic bloodstream was established its maximum concentration in blood plasma was observed already 3.6 1.2 hours after administration, and its slow removal from the systemic bloodstream the half-life was about 19 h, the average retention time was about 29 h. Phenosanic acid with different degrees of intensity was distributed to all the examined organs and tissues: kidneys liver brain omentum muscle, and invariably excreted in a small amount with urine and feces, about 0.04% and 5.5%, respectively.&#x0D; CONCLUSIONS: As a result of the study, it was found that phenosanic acid is characterized by rapid absorbtion into the systemic bloodstream and a long stay in it invariably, which may be due to the peculiarities of its binding to blood plasma proteins and relatively high metabolic stability, revealed during the corresponding in vitro tests. The study of the permeability and transport of phenosanic acid showed that it can presumably be attributed to compounds with medium permeability and is not a substrate for the transport protein P-glycoprotein (P-gp). The study of tissue availability of phenosanic acid confirmed its entry into peripheral tissues, including the brain, which is the area of implementation of the anticonvulsant effect.

Вплив препарату «Біофосфомаг» на біохімічні показники крові за умов індукованого оксидативного стресу у щурів

The study was aimed to examine the effects of the Biophosphomag medication on biochemical parameters of blood under induced oxidative stress in rats. For this purpose, we used 24 animals weighing 200±20 g. The animals were divided into 4 groups of 6 animals in each one and kept on a standard diet with access to water ad libitum. The 1st group was an intact control without oxidative stress and its correction; the 2nd was a control with induced oxidative stress and without its correction. The 3rd group received a 1% solution of magnesium sulfate intragastrically. The animals of the 4th group were administered Biophosphomag (a combined medication of magnesium and phosphorus based on casein) in a dose equivalent to magnesium sulfate by magnesium. Oxidative stress was induced with a single intragastric administration of paracetamol. The results of the serum analysis after the intake of medication showed, on the one hand, a decrease in the activity of the enzymes: alkaline phosphatase, alanine aminotransferase, α-amylase, aspartate aminotransferase, lactate dehydrogenase, glucose and TBA-active compounds concentration (P&lt;0.05), and, on the other hand, an increase in the magnesium concentration and catalase activity. The obtained results indicate a higher bioavailability of magnesium in the composition of the Biophosphomag medication than in the composition of magnesium sulfate, which leads to a more significant hepatoprotective effect under conditions of induced oxidative damage to the liver. They can be an argument why Biophosphomag medication should be used in the correction of pathological processes accompanied by oxidative stress or as a source of magnesium with high bioavailability.