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Vol 22, No 3 (2024)
- Year: 2024
- Published: 13.11.2024
- Articles: 8
- URL: https://journals.eco-vector.com/RCF/issue/view/9045
- DOI: https://doi.org/10.17816/RCF.223
Reviews
Prospects for the use of perampanel in the treatment of epilepsy in patients with malignant gliomas of the brain
Abstract
Epilepsy occurs in 35–95% of patients with low-grade malignant cerebral gliomas and in 29–71% of patients with high-grade gliomas. Seizures can be the first manifestation of a malignant cerebral glioma or may develop in the postoperative period and during chemoradiation therapy. This necessitates the use of antiepileptic drugs that can control seizures, ensure seizure prevention, and provide secondary seizure prophylaxis without reducing the effectiveness of anticancer therapy or the patient’s quality of life. The processes of epileptogenesis and oncogenesis are closely interrelated through common developmental mechanisms, with glutamate playing a key role. Increased glutamate secretion is accompanied by elevated expression and activation of its receptors, which raises seizure susceptibility. This is associated with increased levels of brain-derived neurotrophic factor, the number of synapses between peritumoral neurons and glioma cells, and the expression of various growth factors, all of which contribute to tumor progression. In this context, special attention is given to perampanel, a glutamate receptor antagonist and third-generation antiepileptic drug, in the treatment of epilepsy in patients with malignant cerebral gliomas. It has been shown that perampanel not only effectively controls seizures in patients with malignant cerebral gliomas but also suppresses tumor progression. Perampanel can dose-dependently enhance apoptosis and disrupt cell migration in malignant glioma cell lines. A synergistic effect of perampanel in combination with temozolamide has been identified. During chemoradiation therapy, perampanel exerts a protective effect on healthy peritumoral tissues. Adverse drug reactions associated with perampanel use are infrequent and mild. Further research is needed to investigate the anticonvulsant and antitumor efficacy of perampanel for the treatment of epilepsy in patients with malignant brain tumors.
223-236
Cyclotides. Prospects for using violet oxytocin-like substances to create a new generation of pharmacological agents
Abstract
This review article focuses on the use of violets and their derivatives as medicinal agents. Special attention is given to the historical aspects of using the healing properties of violets, as well as the analysis of substances derived from these plants for pharmaceutical production. The article specifically discusses oxytocin-like substances found in violets, particularly cyclotides. Cyclotides are globular microproteins with a unique head-to-tail cyclized backbone stabilized by three disulfide bonds forming a cystine knot. The chemical characteristics of cyclotides make them suitable for use as recombinant scaffolds in the design and development of ligands for G protein-coupled receptors, which are part of the modern generation of drugs. The development of ligands for bradykinin and κ-opioid receptors, which are in demand in modern pharmacology, is described in detail.
237-255
Absorption, distribution, metabolism and excretion of carbon nanostructures
Abstract
The interaction of any substance with the body is determined by several parameters, namely: its adsorption, distribution, metabolism, and excretion (ADME properties). Naturally, this also fully applies to such a class of compounds as carbon nanostructures. They are mostly composed of sp2-hybridized carbon atoms (except for nanodiamonds, which consist of sp3-hybridized atoms). However, they differ significantly in their properties. This review focuses on these differences. It covers fullerenes, nano-onions, carbon nanotubes, carbon nanohorns, graphene and its derivatives, as well as nanodiamonds.
257-276
Hypoxic irreversible brain cells damage, associated risk factors and antihypoxants
Abstract
It is reported that in the final stage of many diseases the immediate cause of biological death in humans and warm-blooded animals is hypoxic irreversible damage to brain cells. This explains the fact that to prevent biological death in all critical conditions without exception, inhalation with breathing gases containing oxygen has long been successfully used. This is also why oxygenation of the blood is considered one of the main conditions for preserving human life in all critical situations and forms the basis of emergency medical care in the intensive care unit. However, inhalation of oxygen gas and increasing blood oxygen saturation should be carried out as early as possible, and more precisely — before the onset of the stage of hypoxic irreversible damage in brain cells. The fact is that after the onset of irreversible damage brain cells die even in the presence of oxygen. In this connection, the mechanisms of adaptation of the organism to oxygen deficiency play a great role for longer preservation of brain cells viability and human life in conditions of hypoxemia. In order to increase resistance to hypoxemia, antihypoxants are traditionally used. But they can preserve the viability of brain cells not always, but only if they are introduced into the body before the onset of hypoxic irreversible damage to brain cells and in the case of unused reserves of adaptation to hypoxemia in the body. Risk factors of hypoxic irreversible damage of brain cells are indicated, among which excessively long duration of hypoxemia and hyperthermia are emphasized. It is shown that the most important circumstance for the development of hypoxic irreversible damage of brain cells is not so much the degree of hypoxemia as the degree of hypoxia of brain tissue and its duration, which exceeds the period of human resistance to hypoxia. It has been shown that human resistance to hypoxia can be assessed using the Stange test. It has been reported that fever and local cerebral hyperthermia decrease, and hibernation and local cerebral hypothermia increase, the resistance of brain cells to hypoxia. In this regard, recommendations not only to eliminate fever and local inflammatory processes in the head, but also recommendations to reduce brain temperature are highly appropriate to improve resistance to hypoxia. It is pointed out that among the methods of local therapeutic hypothermia, targeted temperature management is the most advanced. In addition, it is reported that in recent years a new group of promising antihypoxants — alkaline solutions of hydrogen peroxide — has been created. It is shown that hydrogen peroxide is able to decompose very quickly into water and oxygen gas under the action of catalase, which is found in all tissues. The peculiarities of using alkaline solutions of hydrogen peroxide as antihypoxants we all have to study in the future.
277-288
Original study articles
Effectiveness of metformin in combination with intranasal insulin for the treatment of metabolic and hormonal disturbances in adult male rats with metabolic syndrome induced by impaired breastfeeding
Abstract
BACKGROUND: Limiting or temporally stopping breastfeeding can lead to the development of metabolic syndrome in adulthood, which requires the development of approaches for its prevention and correction. One such approach is treatment with metformin or intranasal insulin. Since the targets of these agents differ and may complement each other, it has been suggested that their combined use could be effective.
AIM: To study the effect of a four-week co-administration of metformin (orally, 120 mg/kg/day) and intranasal insulin (1.2 IU/kg/day) in male rats with metabolic syndrome, induced by breastfeeding disruption on postnatal days 19–21, on their metabolic and hormonal parameters.
MATERIALS AND METHODS: The study treatment was compared with monotherapy using the same drugs.
RESULTS: It was found that adult male rats with disrupted breastfeeding developed obesity, dyslipidemia, hyperleptinemia, impaired glucose tolerance, and a reduction in the number of β-cells and the area of pancreatic islets, which are characteristic of metabolic syndrome. Long-term treatment with metformin and its combination with intranasal insulin partially or fully normalized body weight, abdominal fat, and metabolic and hormonal parameters, with the restorative effect of combination treatment on such parameters as body weight, fat mass, glucose tolerance, and blood glycated hemoglobin levels being more pronounced than with metformin alone.
CONCLUSIONS: The results of the study support the use of a combination of metformin and intranasal insulin to normalize metabolic and hormonal parameters in metabolic syndrome induced by breastfeeding disruption in early days of life.
289-300
Increased survival of aquarium fish under acute hypoxia induced by prior intragastric administration of hydrogen peroxide
Abstract
BACKGROUND: A solution of 3% hydrogen peroxide is an over-the-counter oxygen-releasing antiseptic, which forms oxygen foam when interacting locally with the wound surface. Therefore, this drug is widely used for mechanical cleansing of the surface of chronic wounds from purulent masses. The release of oxygen during catalase cleavage of hydrogen peroxide indicates the possibility of achieving anti-ischemic and anti-hypoxic action.
AIM: A study of the effect of intragastric hydrogen peroxide on the resistance of aquarium fish to acute hypoxia.
MATERIALS AND METHODS: Experiments were conducted on 80 adult aquarium fish of the guppy, blue neon, tri-linear parsings, swordtail fish and zebrafish (Danio rerio) breeds. To create acute hypoxia, each fish was placed in a transparent plastic container containing 5, 10 or 20 ml of fresh water at a temperature of +25 - +26 °C together with the fish, after which the container was hermetically sealed. Then, the motor activity of the fish's body, the respiratory movements of the gill arches, the opening of the oral cavity, the fluctuations of the fins and the dynamics of their coloration were monitored until the complete final immobilization of the fish and their death. Immediately before the experiment, 0.05 or 0.1 ml of fresh water in the control series and 0.05 ml or 0.1 ml of 0.05% hydrogen peroxide solution in the experimental series were injected into the stomach of the fish. The liquid was injected into the fish's stomach using a gastric mini-probe connected to an insulin syringe.
RESULTS: It is shown that aquarium fish retain their viability in a small volume of fresh water inside a hermetically sealed container for a limited period of time, since fish continuously consume oxygen dissolved in water, thereby deepening hypoxia. At the same time, after sealing the container, the fish very quickly assume a stationary state, in which they remain for a certain period of time until their death. However, just before death, the immobility of the fish is disturbed. At the same time, the fish suddenly appear convulsive body movements, active movements of pectoral fins, mouths and gill arches, pectoral fins change their color, after which the fish defecate into the water. The results showed that the preliminary injection of 0.05 or 0.1 ml of 0.05% hydrogen peroxide solution into the stomach of fish prolongs the period of immobility of fish in hypoxia by an average of 20%. In all likelihood, the immobile state of fish is part of the complex of their adaptive adjustment to the cessation of oxygen supply to the water and reflects the availability of reserves of adaptation to hypoxia. The fact is that the absence of muscle contractions stops the muscles from using oxygen, which they use to generate energy. It is assumed that inside the stomach, hydrogen peroxide is absorbed into the blood, where, under the action of the enzyme catalase, it is split into water and gaseous oxygen, which replaces oxygen in the gills in the absence of oxygen in the surrounding water.
CONCLUSIONS: Under model conditions, it was shown that pre-administration of 0.05 or 0.1 ml of 0.05% hydrogen peroxide solution into the stomach of fish increases their survival in conditions of acute hypoxia. Therefore, hydrogen peroxide can be considered as a potential antihypoxant for prolonging life in various types of suffocation, including the final stage of COVID-19.
301-308
Impact of social stress in early ontogenesis on food addiction and ghrelin levels in the hypothalamus of rats
Abstract
BACKGROUND: Factors that can trigger episodes of binge (compulsive) eating include psychological and physical stress. Our studies have shown that maternal deprivation in early ontogenesis leads to an increase in elements of gambling addiction in the Iowa Gambling Task test. This raises the question of the role of maternal deprivation in the development of other types of non-chemical addictions, particularly food addiction.
AIM: To study the role of ghrelin in the manifestation of food addiction elements in rats subjected to maternal deprivation in early ontogenesis.
MATERIALS AND METHODS: Wistar rats were separated from their mothers for 180 minutes daily from day 2 to day 12 after birth. Male rats aged 90–100 days were used in the experiments. To induce compulsive overeating, the animals were given a high-carbohydrate diet (a mixture based on chocolate paste) for 1 hour every third day for 1.5 months. Fifteen minutes before feeding, the chocolate paste was placed within 5 cm of the rat’s reach with visual contact. After compulsive overeating was established, the number and area of ghrelin-producing neuroendocrine cells in the hypothalamus were analyzed using immunohistochemistry in intact rats and animals subjected to maternal deprivation stress.
RESULTS: It was shown that intermittent consumption of the chocolate mixture predicted overeating in rats, independent of weight gain or obesity, as a result of compulsive overeating. In studying the effect of maternal deprivation on chocolate consumption, it was found that the average daily consumption in the maternal deprivation group increased (p < 0.001) compared to the control group. However, there was no significant difference in standard food consumption between the maternal deprivation and control groups. The number and area of ghrelin-producing neuroendocrine cells in the lateral portion of the medial arcuate nucleus of the hypothalamus were reduced in rats after maternal deprivation.
CONCLUSIONS: It was concluded that early psychogenic stress from maternal deprivation causes a dysregulation of the ghrelin system, contributing to elements of food addiction in rats.
309-318
Clinical pharmacology
Influence of pharmacotherapy on function of biotransformation of xenobiotics liver in patients with neuropsychiatric disorders
Abstract
BACKGROUND: The mechanisms of drug interactions of psychotropic drugs are associated with the processes of drug biotransformation by enzymes of microsomal oxidation of cytochrome P-450 in the liver. Various drugs can increase or decrease the activity of enzymes of the cytochrome P450-dependent system.
AIM: To evaluate the effect of pharmacotherapy with psychotropic drugs: alprazolam, bromazepam, lithium carbonate on the metabolic rate of the model substrate antipyrine in saliva in patients with neuropsychiatric disorders; the effect of the enzyme-inducing activity of the original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in healthy volunteers.
MATERIALS AND METHODS: 34 male patients were divided into three groups according to the nosological forms of diseases according to ICD-10: Group 1 — heading F43.23 and F43.25; 2 — F06.61; 3 — F41.2. Patients in the group 1 were prescribed alprazolam, in the 2 — bromazepam, in the 3 — lithium carbonate, for a course of 21 days. The comparison group consisted of 10 healthy volunteers. The original anticonvulsant was prescribed to the volunteers. Determination of the pharmacokinetics of antipyrine parameters as a test witness of the processes of elimination from the body was carried out in saliva before and after the end of therapy at a dose of 10 mg/kg once.
RESULTS: Alprazolam administration by patients of group 1 at a dose of 0.5–1.5 mg/day for 21 days did not significantly affect the pharmacokinetic parameters of antipyrine: T1/2, Clt, AUC. Alprazolam did not change the elimination of antipyrine from the saliva of patients. In patients of the group2, who received bromazepam at a dose of 6–12 mg / day,
a background decrease in T1/2, an increase in Clt, a decrease in AUC due to concomitant therapy were noted. Comparison of the pharmacokinetic parameters of antipyrine under the influence of bromazepam with background values not reveal significant differences. Therapy with lithium carbonate at a dose of 500–1000 mg/day in patients of the group 3 did not change the parameters of antipyrine elimination. The obtained data indicate that the drugs do not affect the activity of liver microsomal oxidation in patients. The study of the effect of 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in volunteers revealed a diametrically opposite result: a significant decrease in T1/2 by 2 times, an increase in Clt and a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects and indicates the induction of liver microsomal oxidation.
CONCLUSIONS: Pharmacotherapy using the studied psychotropic drugs in patients is not associated with the induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. The original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea stimulated the induction of liver microsomal oxidation in volunteers.
319-334
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