Olga G. Afanasyeva

Разработка новых анксиолитических препаратов имеет важное значение, поскольку в настоящее время в развитых странах растет число заболеваний, связанных с тревожными расстройствами, а препараты для лечения таких заболеваний вызывают огромное число побочных эффектов, особенно при систематическом употреблении, что привлекает большое внимание к их безопасности. 4,10-Диморфолинацетил-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазаизовюрцитан перспективен в качестве анксиолитического средства с низкой токсичностью. Высокая вероятность проявления 4,10-диморфолинацетил-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазаизовюрцитаном анксиолитической активности была рассчитана с помощью интернет-платформы Pass-online. В данной статье рассматривается его способ получения с выходом 83 % и чистотой 99,6 %, а также биологические исследования in vivo, которые подтверждают точность прогноза in silico.

Introduction: The study was aimed at a comparative analysis of the anti-inflammatory and analgesic activities of diterpene alkaloid songorine obtained from Aconitum barbatum and its cell culture. Materials and Methods: Experiments were performed on 60 male mice of the CBA line. The object of the study was the diterpene alkaloid of songorine (25 µg/kg) isolated from Aconitum barbatum, as well as obtained from the callus culture of cells. Comparative study of analgesic and anti-inflammatory activities of the alkaloid obtained from different sources was carried out under conditions of the formalin test and abdominal constriction test. Diclofenac sodium (10 mg/kg) and paracetamol (85 mg/kg) were used as comparison drugs. Control animals received distilled water. All substances were administered to mice per os for 5 days, the last time – 1 hour before the onset of the damaging effect. Results and Discussion: Under the formalin test conditions, the analgesic activity of songorine from both sources was manifested in the second phase of pain response. The anti-inflammatory activity in this model of both “standard” and ”culture” songorine was comparable to that of diclofenac sodium. Probably, pharmacological activity of alkaloid in the formalin test is provided by suppression of proinflammatory mediators and TRPA1-receptors. In the abdominal constriction test, all investigated substances showed a pronounced analgesic effect maximum under the action of songorine in vitro. In addition, songorine from both sources, in contrast to the reference drug, provided a reliable phlogolytic effect. Probably, the pharmacological activity of songorine in this model is provided by its suppressive action against endogenous mediators of pain and inflammation and of TRPV1-receptors. Conclusion: Comparative analysis of the analgesic and anti-inflammatory effects of songorine (25 µg/kg) from Aconitum barbatum after a 5-dose regimen demonstrated comparability with “culture” songorine (25 µg/kg).

Introduction: This article studies the wound healing activity of the flavonoid schaftoside – apigenin -6-C-β-D glucopyranosyl 8-C-α-L arabinopyranoside (C26H28O14) isolated from the above-ground part of Lyсhnis chalcedonica L. Materials and Methods: The experiments were carried out on sexually mature mongrel male CD-1 mice. The wound healing effect of schaftoside was studied on a model of a plane skin wound. Schaftoside was applied externally (topically) in the form of an aqueous solution using a pipette of 100 mcl per wound at concentrations of 0.1 uG/mL, 1.5 uG/mL, 3.0 uG/mL, one time per day during the entire period of wound healing from the first day after the wound had been induced until its complete epithelialization. Aloe juice (100 mcL per wound) was used as a positive control. A solvent (water) – 100 mcL per wound – was applied to control animals. Results and Discussion: The results of our study on the model of a plane skin wound showed that the compound schaftoside isolated from Lyсhnis chalcedonica, when applied externally (topically) at concentrations of 0.1 uG/mL, 1.5 uG/mL, 3.0 uG/mL, contributes to a significant reduction in the size of plane skin wounds, comparable to the action of aloe juice (the comparison drug). The wound healing effect is more pronounced at the first, second, and third weeks of the healing process, i.e. at the stage of inflammation, proliferation, and activation of the repair process. Under the influence of schaftoside at a concentration of 3.0 uG/mL, a more complete epithelialization was recorded than in the group where the comparison drug (aloe juice) was applied. Conclusion: Our study for the first time shows a pronounced wound healing effect from aqueous solution of the flavonoid schaftoside from Lyсhnis chalcedonica on the model of a plane skin wound in mice. Graphical Abstract

Изучение фармакологической активности на моделях соматогенной боли различного генеза (при термической, висцеральной боли, механической компрессии) выявило высокую обезболивающую активность впервые синтезированного вещества 4-(3,4-дибромтиофенилкарбонил)- 10-(2-этоксиацетил)-2,6,8,12-тетраацетил-2,4,6,8,10,12гексаазатетрацикло[5,5,0,03,11,05,9]додекана (М3), сравнимую и/или превышающую эффект трамадола. Показано, что новая молекула из класса гексаазаизовюрцитанов эффективно блокирует ноцицептивные реакции на супраспинальном, спинальном и периферическом уровнях организации болевой чувствительности. Полученные результаты подтверждают возможность разработки фармакологически активных молекул на основе высокоэнергетического вещества гексаазаизовюрцитана, что является отечественным приоритетным направлением в мировой фармации.

The aim of the study was to assess the probability of developing withdrawal syndrome caused by discontinuation of 5-day administration of thiowurtzine with naloxone challenge test in the experiment.Materials and methods. The test sample of the analgesic “Thiowurtzine, capsule 120 mg” served as the study object. The active pharmaceutical ingredient is an organic, low molecular weight compound 4-(3,4-dibromothiophene carbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo [5,5,0,0^3,11,0^5,9]dodecane that was first synthesized according to computer modeling results at the IPCET SB RAS (Biysk).The likelihood of developing physical dependence was explored by per os administration of thiowurtzine and the reference drug tramadol twice a day for 5 days as follows: 1) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg; 2) at 9 a.m. – thiowurtzine 50 mg / kg and tramadol 10 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 3) at 9 a.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg, at 3 p.m. – thiowurtzine 75 mg / kg and tramadol 15 mg / kg; 4) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg; 5) at 9 a.m. – thiowurtzine 100 mg / kg and tramadol 20 mg / kg, at 3 p.m. – naloxone 10 mg / kg subcutaneously.In all the groups, the intensity of the withdrawal syndrome was studied by specific features in outbred male CD1 mice. During one hour following the naloxone injection, health of mice was assessed according to dominant abstinence components and recessive traits of mild withdrawal syndrome. Two hours after the naloxone injection, the number of mice with negative body weight gain was determined. 24 hours after discontinuation of test compound administration, the open-field test was used to determine the impact on animal behavioral patterns (horizontal and vertical motor and exploratory activity, emotionality and its vegetative manifestations). The hot plate test was carried out to measure the analgesic activity (55˚). The criterion of the withdrawal syndrome severity was a decrease in the number of jumping reactions, changes in the general condition of the animals, stimulation of motor activity, manifestations of hyperalgesia, and a decrease in body weight.Results. No dominant abstinence components and recessive signs of withdrawal syndrome were detected in animals from the thiowurtzine groups. The data obtained in the study (orientation and exploratory behavior, motor activity, emotionality and its vegetative manifestations, grooming, etc.) allow to conclude that thiowurtzine causes no physical dependence in animals after discontinuation of its 5-day administration with naloxone challenge test, as opposed to the reference drug naloxone. A positive disinhibition effect of this analgesic was revealed due to the activated orientation and exploratory behavior (stress caused by the new environment) in the conditions of the open-field test. The animals showed no manifestations of hyperalgesia in the hot plate test. The animals treated with thiowurtzine did not demonstrate any changes in the body weight.Conclusion. The obtained results prove that thiowurtzine is a non-narcotic analgesic. It evokes no side effects typical of opioid analgesics (tramadol), including development of physical dependence and withdrawal syndrome following naloxone challenge test. Previous in vivo and in silico studies (docking, molecular modeling, molecular dynamics simulation) on the multi-target mechanism of thiowurtzine explain the absence of its morphine-like effect by the fact that the major targets of the analgesic are TRPA1 receptors and voltage-gated Ca 2+ channels. With a high degree of probability, the conclusions made herein predict no drug abuse development when thiowurtzine is used in the clinical setting. Absence of ulcerotoxicity found earlier will enable to administer thiowurtzine in long-term cycles for chronic pain syndrome.

Анальгетическое действие производного гексаазаизовюрцитана на моделях соматической боли, вызванной активацией TRPA1- и TRPV1-ионных каналов

The antidepressant, psychostimulant, and nootropic effects of a composition of major and trace elements including KCl, RbNO₃, magnesium sulfate, and zinc sulfate were studied on the models of behavioural despair (Porsolt test) and conditioned passive avoidance test. The preparation was found to shorten the immobilization time in the Porsolt test and promote retention of the conditioned passive avoidance. The most pronounced psychostimulant effect of the substance was observed at a dose of 4.68 mg/kg and the most pronounced antidepressant effect was found at a dose of 18.72 mg/kg. Maximum nootropic activity of the preparation was found at a dose of 93.6 mg/kg.

We studied the effect of a composition of major and trace elements including calcium chloride, sodium chloride, iron (II) sulfate, zinc sulfate, chromium (III) chloride, and potassium bromide on orientation and exploratory behavior and conditioned response of animals in the open field test and conditioned drinking response in a multiple T-maze with three junctions. The test compound exhibited psychostimulant and nootropic activities.