Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we investigated its preclinical profile in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency. The peptide effectively inhibited (IC₅₀ ~ 19 nM) calcium response of muscle nAChR evoked by 30 μM (EC₁₀₀) acetylcholine but was less potent (IC₅₀ ~ 3 μM) at α7 nAChR activated by 10 μM (EC₅₀) acetylcholine and had a low affinity to α4β2 and α3-containing nAChR, as well as to GABA_A or 5HT₃ receptors. Its muscle relaxant effect was demonstrated at intramuscular injection to mice at doses of 30–300 µg/kg, 30 µg/kg being the initial effective dose and 90 µg/kg—the average effective dose. The maximal muscle relaxant effect of Az was achieved in 10 min after the administration and elimination half-life of Az in mice was calculated as 20–40 min. The longest period of Az action observed at a dose of 300 µg/kg was 55 min. The highest acute toxicity (LD₅₀ 510 μg/kg) was observed at intravenous injection of Az, at intramuscular or intraperitoneal administration it was less toxic. The peptide showed practically no immunotoxic, allergenic or mutagenic capacity. Overall, the results demonstrate that Az has good drug-like properties for the application as local muscle relaxant and in its parameters, is not inferior to the relaxants currently used. However, some Az modification might be effective to extend its narrow therapeutic window, a typical characteristic and a weak point of all nondepolarizing myorelaxants.

To preclinically study the effectiveness of new antihypertensive drugs, various animal hypertension models are used. However, most of them do not correspond to primary hypertension, which develops in people with age. We used male Wistar rats of 4, 10, 12 and 18 months old. The animals were divided according to systolic blood pressure (SBP) into normotensive (SBP ≤ 114 mmHg) or hypertensive (SBP ≥ 115 mmHg). Within hypertensive animals, two cohorts were distinguished—with SBP below and above 125 mmHg. The animals received 100 µg/kg of taxifolin intraperitoneally for 7 days. A significant difference was shown between animals with SBP above and below 115 mmHg, as well as between cohorts of hypertensive animals with SBP above and below 125 mmHg within each age. The number of animals with elevated SBP increased with age both for clusters with an SBP above 115 mmHg and for cohorts with an SBP above 125 mmHg. Administration of taxifolin led to a significant decrease in the SBP only in hypertensive animals. A physiological model of age-related hypertension was obtained in male Wistar rats. It has been shown that hypertension develops and worsens with age. In preclinical studies, it should be taken into account that drugs may have different effects depending on the initial SBP of the animals.

Background/Objectives: Intratracheal administration of bleomycin (BLM) to laboratory rodents is a standard, widely used technique used to model pulmonary fibrosis (PF). BLM, as a modeling agent, is produced mainly in the form of two salts—sulfate and chloride. We compared the results of modeling PF in SD rats by intratracheal administration of BLM sulfate and BLM chloride. Methods: Healthy mature male SD rats were used. PF was modeled by intratracheal administration of BLM sulfate and BLM chloride at a dose of 3 mg/kg. The criteria for the development of PF included body weight gain, changes in respiratory parameters, relative lung weight, cellular composition of broncho-alveolar fluid (BALF), histological assessment of the severity of PF with trichrome Masson staining. Results: Intratracheal administration of both BLM salts led to the development of pronounced PF, which was determined by changes in all of the measured parameters relative to control animals. There were no significant differences between the BLM sulfate and BLM chloride groups in body weight gain, hydroxyproline content, and histological evaluation. However, significant differences were identified in the cellular composition of BALF—a significant increase in alveolar macrophages and neutrophils levels in animals treated with BLM sulfate. Conclusions: Intratracheal administration of both BLM salts led to the development of severe PF; however, the inflammatory process in animals receiving BLM sulfate was more pronounced and prolonged than in animals receiving BLM chloride, which in the former, when observed more than 21 days after modeling, can lead to more severe PF.

218 It is known that presowing treatment of plants with the growth regulator melaphene (melamine salt of bis(oxymethyl)phosphinic acid) at low and ultralow concentrations significantly increases the yield of cereals, legumes, and crucifers, enhancing the stress-resistance of plants under adverse environmental conditions [1, 2]. For substantiated and efficient application of this agent, it is necessary to investigate in detail the mechanism of its action at the molecular and cellular levels. It was shown earlier that the effect of melaphene is determined by the activation of metabolic pathways in stress, which correlated with changes in the microviscosity of annular lipids in cell membranes [3‐5]. The goal of this work was to study the fine structure of model phospholipid membranes under the treatment of melaphene. The range of tested melaphene concentrations was significantly broadened. An additional goal of this study was to reveal possible side effects of melaphene. We studied the interaction of melaphene with the liposomes formed from the individual neutral phospholipid dimyristoylphosphatidylcholine (DMPC) and egg lecithin, which represents a mixture of natural phospholipids. The results of differential microcalorimetric and X-ray diffraction analyses showed that melaphene changes the domain structure of neutral phospholipids in the membrane but has no effect on the next organizational level—the total size of bilayers in multilamellar liposomes formed of natural phospholipids. The effect of melaphene in a broad concentration range (10 ‐21 to 10 ‐3 M) on the conformational rearrangements of the bilayers was assessed by measuring the small-angle X-ray diffraction of egg lecithin liposomes and the thermostability of DMPC liposomes as described in [6‐10]. Small-angle X-ray diffraction analysis of liposomes was performed as described in [8] with some modifications. X-ray diffractograms of dispersed liposomes of phospholipid membranes were obtained using a smallangle X-ray diffractometer equipped with a linear coordinate detector [9]. Diffractograms of dispersed liposomes were normalized by the maximum intensity at the peak of the first diffraction maximum, and the collimation correction for the height of the X-ray beam and detector window was introduced according to [10]. Two diffraction maxima could be distinguished on the liposome dispersion diffractograms of the samples containing melaphene at concentrations 0, 10 ‐21 , 10 ‐18 , 10 ‐12 , and 10 ‐6 M, which represented the first and second orders of reflection of ordered membrane multilayers in liposomes. As seen in Fig. 1, the diffractogram patterns of the studied samples of liposome dispersion coincided, indicating that the membrane structure was the same in all liposome samples. The membrane periodicity interval in liposomes ( D ) was found to be 6.9 nm. The electron density profiles of lipid membranes in the liposomes (Fig. 2) were used to determine the thickness of one membrane, which was calculated as the distance between the electron density peaks corresponding to the position of polar groups in lipids. The membrane thickness in all liposome preparations in the presence of different melaphene concentrations was approximately 4 nm. Thus, the results of small-angle X-ray diffraction analysis showed that melaphene in a broad concentration range ( 10 –21 to 10 –6 M) has no marked effect on the structure of lipid membranes. Differential scanning microcalorimetry of DMPC liposomes was performed by the standard method using a DASM-4 microcalorimeter; the results were subsequently processed using the Microcal Origin 5.0 software [7]. It was found that melaphene at low and ultralow concentrations affects the fine structure of

The capacities of relatively nontoxic lipopolysaccharide (LPS) from Rhodobacter capsulatus PG and highly potent LPS from Salmonella entericaserovar Typhimurium to evoke proinflammatory cytokine...