Distribution, excretion and metabolic pathways of a single parenteral administration of kappa-opioid receptor agonist RU-1205

The purpose was to study the pharmacokinetic properties of RU-1205 with the previously identified kappa-agonistic and analgesic effects after parenteral administratio

Effects of a New Kappa Agonist (Fluorophenyl Derivative of Imidazo[1,2-<i>а</i>]benzimidazole) on the Rat Genome

Selective kappa-opioid receptor (KOR) agonists are considered a promising group of substances for developing opioid analgesics characterised with an original mechanism of action without the risk of respiratory depression and drug addiction. Previous studies identified a fluorophenyl derivative of imidazo[1,2-a]benzimidazole (RU-1205) with a KOR-based mechanism of analgesic action established in in vitro and in vivo experiments.The aim of the study was to assess the effect of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole dihydrochloride on the level of DNA damage in rats after a single subcutaneous injection.Materials and methods. The study was conducted in adult white outbred laboratory rats of both sexes. DNA damage was estimated using the comet assay. The study involved a single subcutaneous injection of an aqueous solution of RU-1205 in three doses: 1, 10, and 100 mg/kg. The authors used intraperitoneal methyl methanesulfonate (40 mg per kg of animal body weight) as a positive control and 0.9% NaCl  (100 μL per 100 g of animal body weight) as a negative control.Results. A single subcutaneous injection of RU-1205 to rats did not produce a significant dose-dependent increase in % tail DNA when compared with the state of   the corresponding organ/tissue cell genome in negative control animals after normal saline administration at the same time points. In the negative control groups, % tail DNA in cells of various organs/tissues ranged from 1.83% to 3.82% (median values [25–75%]). On the contrary, the administration of 40 mg/kg of genotoxic methyl methanesulfonate led to an increase in damaged DNA in all studied organs and tissues when compared with negative control animals.Conclusions. The study of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a] benzimidazole dihydrochloride genotoxicity demonstrated that a single subcutaneous injection of 1, 10, or 100 mg/kg of RU-1205 to rats did not damage the cell genome of the studied organs

Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-120

Влияние нового каппа-агониста (фторфенилпроизводное имидазо[1,2-а]бензимидазола) на геном крыс

Selective kappa-opioid receptor (KOR) agonists are considered a promising group of substances for developing opioid analgesics characterised with an original mechanism of action without the risk of respiratory depression and drug addiction. Previous studies identified a fluorophenyl derivative of imidazo[1,2-a]benzimidazole (RU-1205) with a KOR-based mechanism of analgesic action established in in vitro and in vivo experiments.The aim of the study was to assess the effect of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a]benzimidazole dihydrochloride on the level of DNA damage in rats after a single subcutaneous injection.Materials and methods. The study was conducted in adult white outbred laboratory rats of both sexes. DNA damage was estimated using the comet assay. The study involved a single subcutaneous injection of an aqueous solution of RU-1205 in three doses: 1, 10, and 100 mg/kg. The authors used intraperitoneal methyl methanesulfonate (40 mg per kg of animal body weight) as a positive control and 0.9% NaCl  (100 μL per 100 g of animal body weight) as a negative control.Results. A single subcutaneous injection of RU-1205 to rats did not produce a significant dose-dependent increase in % tail DNA when compared with the state of   the corresponding organ/tissue cell genome in negative control animals after normal saline administration at the same time points. In the negative control groups, % tail DNA in cells of various organs/tissues ranged from 1.83% to 3.82% (median values [25–75%]). On the contrary, the administration of 40 mg/kg of genotoxic methyl methanesulfonate led to an increase in damaged DNA in all studied organs and tissues when compared with negative control animals.Conclusions. The study of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-a] benzimidazole dihydrochloride genotoxicity demonstrated that a single subcutaneous injection of 1, 10, or 100 mg/kg of RU-1205 to rats did not damage the cell genome of the studied organs.В качестве перспективной группы веществ для создания опиоидных анальгетиков с оригинальным механизмом действия без риска развития респираторной депрессии и наркотической зависимости рассматриваются каппа-селективные агонисты. В предыдущих исследованиях было выявлено соединение РУ-1205 (фторфенилпроизводное имидазо[1,2-а]бензимидазола) с установленным в экспериментах in vitro и in vivo каппа-рецепторным механизмом анальгетической активности.Цель работы: оценка влияния дигидрохлорида 9-(2-морфолиноэтил)-2-(4-фторфенил)имидазо[1,2-а]бензимидазола  на  уровень  повреждений  ДНК   у   крыс при однократном подкожном введении.Материалы и методы: исследование выполнено на половозрелых белых беспородных лабораторных крысах обоего пола. Повреждения ДНК учитывали методом ДНК-комет. Использовалась схема c однократным подкожным введением водного раствора субстанции РУ-1205 в трех дозах: 1, 10 и 100 мг/кг. В качестве положительного контроля использовали метилметансульфонат в дозе 40 мг/кг внутрибрюшинно, в качестве отрицательного  контроля  —  0,9%  раствор  NaCl (100 мкл на 100 г массы животного).Результаты: при однократном подкожном введении крысам РУ-1205 дозозависимо не увеличивает показатель %ДНК в хвостах комет. Изменения не носят достоверного характера по сравнению с состоянием генома клеток соответствующих органов/тканей животных, получавших в эти же сроки физиологический раствор. %ДНК в хвостах комет в клетках различных органов/тканей в группах животных отрицательного контроля составляет 1,83–3,82% (медианное значение [25–75%]). Введение генотоксиканта метилметансульфоната в дозе 40 мг/кг приводит к увеличению количества поврежденной ДНК по сравнению с группой отрицательного контроля во всех исследуемых органах и тканях.Выводы: в результате исследования генотоксических свойств дигидрохлорида 9-(2-морфолиноэтил)-2-(4-фторфенил)имидазо[1,2-а]бензимидазола установлено, что при однократном подкожном введении крысам в дозах 1, 10, 100 мг/кг РУ-1205 не оказывает повреждающего действия на геном клеток исследуемых органов

Adjuvant therapy in premenopausal women with hormone-dependent breast cancer

In recent years, several studies have indicated that aromatase inhibitors (AIS) combined with a gonadotropin-releasing hormone agonist (GnRH agonist) are safe and effective in premenopausal patients with hormone receptor positive (HR+) breast cancer (BCA). The ABCSG-12 trial has shown a comparable DFS for 3-eyar adjuvant therapy with anastrazol-goserelin and tamoxifengoserelin. However a combined analysis of the data from SOFT and TEXT trials demonstrated that compared with tamoxifen plus ovarian suppression, adjuvant endocrine therapy with exemestane plus GnRH agonist (Triptorelin) in premenopausal patients with a significant improved DFS and an extended interval without distant recurrence. The differing results emerging from ABCSG-12 and the TEXT and SOFT trials misht be related to higher statistical power in the combined analysis