Elena P. Zueva

Из надземной части S. cupuliformis Nakai & Kitagawa получены нативный этанольный экстракт и бутанольный комплекс. Методом ВЭЖХ в экстрактах идентифицированы и количественно определены флавоноиды и экдистероиды, включая 20-гидроксиэкдизон. Установлено, что экстракция бутиловым спиртом приводит к увеличению доли экдистероидов: содержание 20-гидроксиэкдизона возросло в 4 раза при одновременном снижении концентрации флавоноидов. В эксперименте на мышах линии C57Bl/6 изучено влияние нативного этанольного экстракта и бутанольного комплекса из S. cupuliformis на развитие карциномы легких Льюис (LLC) и эффективность терапии циклофосфамидом. Показано, что курсовое изолированное введение бутанольного комплекса в дозе 100 мг/кг мышам с LLC вызывало увеличение массы лёгких. Применение этанольного экстракта в дозе 50 мг/кг на фоне однократного внутрибрюшинного введения циклофосфамида (125 мг/кг) приводило к снижению антиметастатического эффекта цитостатика.

Aim. To assess the anti-inflammatory and gastroprotective effects of ethowurtzine compared to the reference drug diclofenac in a rat model of chronic inflammation; to evaluate the influence of ethowurtzine on nitric oxide production as a possible mechanism of its anti-inflammatory effects.Materials and methods. The object of the study was a new patented ethowurtzine from the class of hexaazaizowurtzitane derivatives with an acceptable safety profile.The gastroprotective and anti-inflammatory effects of ethowurtzine compared to diclofenac were studied in a model of chronic inflammation using 69 female SD rats. The compound (12.5–100 mg / kg) and a non-selective COX inhibitor diclofenac (5 mg / kg) were administered intragastrically for 7 days, 1 hour before subcutaneous implantation of a cotton swab. On day 8, the proliferative response (%), the exudative response (%), and the ulcerogenic effect of the compounds were assessed.Nitric oxide (NO) synthesis by macrophages obtained from peritoneal cavity of 25 C57Bl/6 mice (in vitro inflammation model) was evaluated by the concentration of nitrites in the cell supernatant after incubating cells in the presence of ethowurtzine and / or lipopolysaccharide (LPS) for 48 hours. The classical MTT test (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT, Sigma, USA)) was used to assess the effects of ethowurtzine on macrophage proliferation.Results. A comparative study of ethowurtzine and diclofenac in a rat model of chronic inflammation revealed the predominant anti-exudative effect of the new substance and a suppressive effect on granulation tissue proliferation comparable to that of NSAID.The macroscopic examination of the gastric mucosa in rats receiving ethowurtzine did not reveal any ulcer damage. On the contrary, in 30% of the rats receiving diclofenac, the severity score of ulcer was 2. In the in vitro inflammation model, the addition of LPS to the macrophage culture resulted in a significant increase in NO synthesis. The introduction of ethowurtzine at different concentrations together with LPS dose-dependently reduced the NO production. A statistically significant decrease in the NO synthesis was noted at high doses of the test substance compared to the group of isolated LPS use. However, the introduction of ethowurtzine at different concentrations together with LPS did not cause statistically significant changes in the proliferation of macrophages compared to the group with the isolated LPS use.Conclusion. The newly synthesized ethowurtzine had a pronounced anti-inflammatory effect and caused a significant decrease in granulomatous infiltration and exudative edema in the chronic inflammation model. Suppression of the NO synthesis is one of the possible mechanisms in the anti-inflammatory effect of ethowurtzine. The obtained data allow to suggest possible administration of the new patented analgetic ethowurtzine in chronic pain treatment associated with inflammation.

Biologically active compounds of natural or synthetic origin have a complex structure and generally contain various structural groups among which polycyclic cage amines are found. Hexaazaisowurtzitanes are representatives of these amines and studies on their biological activity began less than two decades ago, starting with research on the environmental impact of CL-20. This research helped to evaluate the risks of potential pollution in the habitat environments of living organisms and determine whether the chemical compounds in question could be utilized in pesticides, herbicides, fungicides, or medicinal drugs. The nomenclature of hexaazaisowurtzitane compounds has recently been expanded significantly, and some of them have demonstrated promise in the design of medicinal drugs. This paper review studies the pharmacological activity of the acyl derivatives of hexaazaisowurtzitane. Most of the compounds have been found to possess a high analgesic activity, providing a solution to the pressing issue of pain management in current pharmacology. Analgesic drugs currently used in the clinical practice do not meet all of the efficacy and safety requirements (gastro-, nephro-, hepato-, haematotoxicity, etc.). The material presented in the seven sections of this paper highlights information about hexaazaisowurtzitane derivatives. Furthermore, they have been observed to exhibit anti-inflammatory, anticonvulsant, antihypoxic, and antimetastatic activities, which render them highly promising for evaluation in various fields of medicinal practice.

Антоцианы относятся к флавоноидным соединениям, входящим в группу полифенолов. Одной из богатых этой группой БАВ является A. melanocarpa (Michx.) Elliott. — рябина черноплодная. Химический анализ показал, что антоциансодержащий комплекс, полученный из плодов А. melanocarpa, состоит из антоцианов, флавоноидов, фенолокислот и катехинов. Доминирующими компонентами являются антоцианы. Накопилось огромное количество данных, доказывающих, что плоды аронии обладают широким спектром фармакологической активности. С целью оценки безопасности применения антоциансодержащего комплекса из плодов A. melanocarpa проведено генотоксическое исследование растительного комплекса с последующим изучением его влияния на мутагенез на модели доксорубицин-индуцированной генотоксичности в клетках костного мозга мышей линии С57Bl/6. Показано, что применение растительного комплекса в дозе 225 мг/кг не оказало влияния на цитогенетические показатели клеток костного мозга животных после одно-, двухкратного введения. Использование антоциансодержащего комплекса привело к снижению повреждения ДНК, вызванного введением доксорубицина, через 24, 48 ч после введения цитостатика. Таким образом, представленные данные о снижении повреждающего действия доксорубицина на ДНК антоциансодержащим комплексом А. melanocarpa могут стать основой для создания препарата-корректора цитостатической терапии злокачественных новообразований.

Описан способ получения перспективного ненаркотического анальгетического средства вещества с выраженной противовоспалительной активностью из класса гексаазаизовюрцитанов. Рассмотрены способы снижения стоимости получения целевого вещества и приведены его полные физико-химические характеристики. Эффективность и безопасность полученного средства показана на нескольких животных моделях.

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.

Оценка эффективности использования фенолсодержащих комплексов из различных частей рябины обыкновенной (Sorbus aucuparia L.) в онкологическом эксперименте

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

Новый анальгетик на основе гексаазаизовюрцитана: возможность использования в онкологической практике