Reviews on Clinical Pharmacology and Drug Therapy

Currently, the targeted delivery of anticancer drugs can significantly increase the effectiveness of therapy, reduce the side effects of systemic chemotherapy, and improve the quality of patients with cancer. This review aimed to summarize data about the domestic antitumor drug 2,4-bis(1-aziridinyl)-6-(2,2-dimethyl-5-hydroxymethyl-1,3-dioxan-5-yl)amino-1,3,5-thriazine (dioxadet), its nanoforms, possibilities of its use in the clinic, and main antitumor nanodrugs clinically introduced in recent years. Library databases (eLibrary, PubMed, CyberLeninka, ResearchGate, Springer, Wiley Online Library, and Elsevier) were searched for relevant information. The literature review summarizes data on the preclinical trials of dioxadet and provides information on its nanoforms, such as nanogels, nanodiamonds, silica particles, and copolymers with lactic and caproic acids. New drug nanoforms open up opportunities to reduce drug side effects and systemic toxicity, maintain optimal therapeutic concentrations, increase the drug circulation time in the blood, and control its release. The possibility of using chemopreparation cytotoxic doses is the main advantage of new nanodrugs. To date, approximately 20 antitumor nanodrugs have been introduced in clinical practice, and some nanodrugs are undergoing preclinical trials or are in various phases of clinical trials. Thus, the development of a new effective nanoform, i.e., dioxadet, makes it possible to ensure targeted drug delivery in higher cytotoxic doses to target cells, increase selective action, and reduce cytostatic toxicity to normal cells.

BACKGROUND: Depressive states are becoming an increasingly common mental disorder and a serious social problem that places a heavy economic burden on society. Increasing data from preclinical and clinical studies indicate that orexins (neuropeptides, also known as hypocretins) and their receptors are involved in the pathogenesis of depression. The orexinergic system regulates disrupted functions in depressive states, such as sleep, reward system, eating behavior, stress response, and monoaminergic regulation. However, the exact role of orexins in behavioral and neurophysiological disorders in depression is still unclear.

AIM: This study aimed to examine the effect of early postnatal stress on the expression of OX1R orexin in the limbic system and the development of anxiety-depressive symptoms in rats.

MATERIALS AND METHODS: Maternal deprivation was used as a model of early postnatal stress (postpartum days 2–12). The animals were divided into the control (n = 20) and maternal deprivation (n = 20) groups. On day 90 of life, the influence of early postnatal stress on the development of anxiety-depressive symptoms in adult rats was analyzed using a package of behavioral tests, namely, raised cruciform maze, forced swimming Porsolt test, and two-bottle test. After the experiments, the animals were killed by decapitation, the brain was extracted and placed in the cold, and brain structures (hypothalamus and amygdala) were isolated, immediately frozen in liquid nitrogen, and stored at a temperature of −80°C for polymerase chain reaction analysis.

RESULTS: In the “raised cruciform maze,” the maternal deprivation group spent less time in the open arms of the maze, and the time spent in the closed sleeves increased relative to the control, which can be assessed as an increase in anxiety levels. In the Porsolt test, the maternal deprivation group had increased immobilization time relative to the control group. In the two-bottle sucrose preference test, the maternal deprivation group demonstrated a decreased preference for sucrose solution, which indicates the development of anhedonia. In the hypothalamus, the mRNA expression level of OX1R significantly decreased in the experimental group compared with that in the control group. A twofold decrease in the mRNA expression level of OX1R was also observed in the amygdala of the experimental group compared with that of the control group.

CONCLUSIONS: Early stress caused by maternal deprivation resulted in a decrease in OX1R orexin expression in the hypothalamus and amygdala and contributed to the development of anxiety-depressive symptoms in rats.

BACKGROUND: The activation of spinal cord NMDA receptors is a key factor in the pathogenesis of acute and chronic pain. Therefore, the use of existing NMDA antagonists in analgesic schemes and the development of new compounds targeting the NMDA receptor complex are gaining attention. New ligands of the glutamate NMDA receptor complex are derivatives of imidazole-4,5-dicarboxylic acid. The conformational rigidity of the molecules of imidazole-4,5-dicarboxylic acid derivatives allows for increased selectivity of interaction and reduced side effects.

AIM: This study aimed to investigate the analgesic effect of new ligands of the glutamate NMDA receptor complex, which are derivatives of imidazole-4,5-dicarboxylic acid, in rats using the tail-flick test and the formalin test.

MATERIALS AND METHODS: The analgesic activity of the compounds was examined in a model of acute somatic (thermal) pain in the tail-flick test and model of somatic pain induced by algogens in the formalin test. The tested compounds (IEM-303 and IEM-2044) were administered intraperitoneally at doses of 5, 10, 15, and 20 mg/kg. Мetamizole was used as the comparison drug.

RESULTS: The experiments demonstrated a significant dose-dependent analgesic effect of the tested compounds on the experimental models of acute pain at doses of 5–20 mg/kg. The tail-flick latency increased by 1.4–1.7 times in the IEM-2044 and IEM-303 groups compared with the value in the control group.

CONCLUSIONS: The analgesic activity of the tested compounds at 10–20 mg/kg doses was comparable to that of metamizole, indicating the prospect of developing these agents and further searching for effective and safe analgesics in this pharmacological class.

BACKGROUND: Rodents are often used as a social isolation model. This study investigated the effects of social isolation on Danio rerio. These animals form groups and social hierarchies and exhibit complex social interactions similar to rodents. The expression of some brain genes of fish reared in isolation was found to be different from individuals reared in a group.

AIM: This study aimed to investigate the effect of kisspeptins on the social behavior of Danio rerio in social isolation.

MATERIALS AND METHODS: Fish were placed in 200-mL measuring cups for 48 h. After the social isolation period, bony fish kisspeptins and mammalian kisspeptin analogs were administered, and their effects were tested. The animal was placed in 1-L individual tanks for 15 min and then in the tank with a glass partition, behind which are a group of congeners. Fish were allowed to approach or swim away from the partition. Two patterns were used to assess behavior: latency time and number of swims to the partition.

RESULTS: Compared with the control group with fish kept in social isolation, reliable differences were observed: The number of swims to the partition after isolation was 1.3 times higher than that in the control group (p < 0.05). After the administration of bony fish kisspeptins Kiss1 and Kiss2, no significant changes in the number of swims to the partition were observed. Moreover, after the administration of KS6 and KS10, the number of swims to the aquarium partition increased 1.6 times (p < 0.01) and 1.8 times (p < 0.001), respectively. After the administration of the comparison drug oxytocin, the number of swims to the aquarium partition increased 1.6 times (p < 0.01) compared with that in the untreated isolated group. The latency time of swimming to the partition increased 2.4 times in the untreated isolated group compared with the control group (p < 0.001). Latency time decreased 2.3 times in the group administered with oxytocin compared with the untreated isolated group (p < 0.001). In the group administered with Kiss1, the latency time decreased 2 times (p < 0.001) compared with that in the untreated isolated group. The latency time decreased 5 times (p < 0.001) after KS10 administration and 3.4 times (p < 0.001) after KS6 administration compared with that in the untreated isolated group.

CONCLUSIONS: Thus, social isolation in Danio rerio reduces communicative behavior. Analogs of mammalian kisspeptin, such as Kiss1, of bony fish and oxytocin normalize the communicative behavior of fish after a period of social isolation to the level of the control group.