Reviews on Clinical Pharmacology and Drug Therapy

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.

Sergei N. Proshin

Vladimir V. Grishin

Alina Ashotovna Dedyan

Cyclotides. Prospects for using violet oxytocin-like substances to create a new generation of pharmacological agents

环肽。利用紫罗兰催产素样物质开发新一代药物的前景

Epilepsy occurs in 35-95% of patients with malignant cerebral gliomas of low malignancy and in 29-71% of patients with gliomas of high malignancy. Seizures can be both the first manifestation of malignant cerebral glioma and appear in the postoperative period and during chemoradiotherapy. This requires the use of antiepileptic drugs, which should control the seizure syndrome, provide control and secondary prevention of seizures, without reducing the response of anti-tumour therapy and the the patient QoL. The processes of epileptogenesis and oncogenesis are closely interrelated through common developmental mechanisms in which glutamate plays a key role. Hypersecretion of glutamate is accompanied by increased expression and activation of its receptors, which increases convulsive readiness. This is accompanied by increased level of brain neurotrophic growth factor, the number of synapses between peritumoral neurons and glioma cells, and increased expression of a number of growth factors, which contributes to tumourous proliferation. In this regard, special attention when treating epilepsy in patients with malignant cerebral gliomas is given to perampanel, a glutamate receptor blocker, a 3rd generation antiepileptic drug. The findings show that perampanel not only effectively controls seizures in patients with malignant cerebral gliomas, but also suppresses tumourous proliferation. Perampanel is able to dose-dependently enhance apoptosis and disrupt cell migration in malignant glioma cell lines. The findings have revealed synergistic effect of perampanel in combination with temozolamide. In conditions of chemoradiation therapy perampanel has a protective effect on healthy peritumoral tissues. Undesirable drug reactions during the use of perampanel are infrequent and insignificant. Additional studies are needed to further research the anticonvulsant and antitumour efficacy of perampanel to treat epilepsy in patients with malignant brain tumours.

Yi Wang

Natalia A. Mufazalova

Lyaysan F. Mufazalova

Nailya V. Ilyasova

Raila R. Muradova

Ikhtiyor E. Kiyomov

Laylo Sh. Davurova

Aleksandr V. Samorodov

Prospects for the use of perampanel in the treatment of epilepsy in patients with malignant gliomas of the brain

恶性脑胶质瘤患者癫痫治疗中普瑞巴林的应用前景

The interaction of any substance with the body is determined by several parameters, namely: its penetration, distribution, transformation and excretion, in other words, ADME properties. Naturally, this fully applies to such a class of compounds as carbon nanostructures (CN). They are mainly formed by sp2-hybridized carbon atoms (with the exception of nanodiamonds formed by sp3-hybridized atoms). However, their properties differ markedly from each other. This review is devoted to examining these differences. This review includes fullerenes, nanoionions, carbon nanotubes, carbon nanohorns, graphene and its derivatives, and nanodiamonds.

Elena V. Litasova

Viktor V. Iljin

Levon B. Piotrovskiy

Absorption, distribution, metabolism and excretion of carbon nanostructures

碳纳米结构的吸收、分布、代谢和排泄

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.

Aleksandr L Urakov

Natalya A. Urakova

Petr D. Shabanov

Hypoxic irreversible brain cells damage, associated risk factors and antihypoxants

缺氧性不可逆脑细胞损伤、相关风险因素及抗缺氧药物

Limitation or short-term interruption of breastfeeding can lead to the development of metabolic syndrome (MS) in adulthood, which requires the development of approaches for its prevention and correction. One of them is treatment with metformin (MF) or intranasally administered insulin (INI). Since the targets of MF and INI are different and these drugs can complement each other, it has been suggested that their combined use is effective. The aim of the work was to study the effect of a four-week co-administration of MF (orally, 120 mg/kg/day) and AI (1.2 IU/kg/day) to male rats with MS caused by interruption of breastfeeding on days 19-21 of postnatal development on their metabolic and hormonal indicators. The study was carried out in comparison with monotherapy with the same drugs. It was found that adult male rats with impaired breastfeeding had obesity, dyslipidemia and hyperleptinemia, impaired glucose tolerance, and a decrease in the number of β-cells and the area of pancreatic islets, which is characteristic of MS. Long-term treatment with MF and its combination with INI partially or completely normalized body weight and abdominal fat, metabolic and hormonal parameters, and the restorative effect of combination therapy in relation to indicators such as body weight and adipose tissue, glucose tolerance and the level of glycated hemoglobin in blood was more pronounced than that of MF monotherapy. This indicates the prospects of using a combination of MF and INI to normalize metabolic and hormonal disorders in MS caused by a deficiency of breastfeeding in early ontogenesis.

Kira V. Derkach

Alexander O Ivantsov

Nataliia E Basova

Alexander O Shpakov

EFFECTIVENESS OF THE COMBINATION OF METFORMIN AND INTRANASAL INSULIN FOR THE CORRECTION OF METABOLIC AND HORMONAL DISTURBANCES IN ADULT MALE RATS WITH METABOLIC SYNDROME INDUCED BY IMPAIRED BREASTFEEDING

二甲双胍与鼻内胰岛素联合治疗对成年雄性代谢综合征大鼠代谢和激素紊乱的纠正效果

Neurodegenerative diseases are characterized by progressive death of nerve cells of certain types with concomitant atrophy of the corresponding parts of the spinal cord or brain, which is symptomatically manifested by severe neurological and cognitive impairment. These diseases can manifest at any age and be caused by both genetic predisposition and inflammatory and autoimmune processes. Diseases of this group are a common cause of disability and mortality. Thus, the development of new effective domestic drugs for their treatment is an important task for the healthcare system of the Russian Federation. In this review is devoted to the analysis of Russian original and bioanalog organic and genetically engineered drugs for the treatment of neurodegenerative diseases that have been registered in recent years or are currently undergoing clinical trials in Russia.

Elena Valerievna Galitsyna

Natalya Alexandrovna Ulyakina

Alexander Borisovich Gusev

Modern Russian drugs for the treatment of neurodegenerative diseases

现代俄罗斯治疗神经退行性疾病的药物

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.

Evgeny Fisher

Aleksandr L. Urakov

The preliminary introduction of hydrogen peroxide into the stomach of aquarium fish increases their survival rate in conditions of acute hypoxia

向水族鱼胃中初步引入过氧化氢可提高其在急性缺氧条件下的存活率

Relevance. Factors that can trigger binge eating episodes include mental and physical stress. Our studies show that maternal deprivation in early ontogenesis causes an increase in elements of gambling addiction in the Iowa Gambling Task test. The question arises about the significance of maternal deprivation in the formation of other types of non-chemical addictions, in particular food addiction. Target. The role of ghrelin in the manifestation of elements of bindge eating in rats exposed to maternal weaning in early ontogenesis was studied. Material and method. Animals were separated from their mother for 180 minutes from days 2 to 12 after birth; males aged 90-100 days were used in the experiments. When developingbindge eating, the animals received a diet high in carbohydrates (chocolate mixture based on Nutella spread) for 1 hour every third day for 1.5 months. 15 min before feeding, chocolate paste was placed within 5 cm of reach with visual contact.After developingbindge eating, we studied the number and area of ​​ghrelin-producing neuroendocrine cells of the hypothalamus in intact rats and animals after maternal deprivation stressusing immunohistochemistry method. Results. Intermittent consumption of a chocolate mixture has been shown to predict binge eating in rats independent of weight gain or obesity, which is a manifestation of binge eating disorder. When studying the effect of maternal deprivation on chocolate consumption, it was shown that the average daily consumption in the maternal deprivation group increased (p0.001) relative to the control group. When studying the effect of maternal deprivation on the consumption of standard food, it was shown that consumption in the maternal deprivation group did not change relative to the control group. The number and area of ghrelin-producing neuroendocrine cells in the lateral portion of the medial arcuate nucleus of the hypothalamus decreased in rats after maternal deprivation. Conclusion. It was concluded that early psychogenic stress of maternal deprivation causes an imbalance of the ghrelin regulatory system with elements of food addiction in rats.

Andrey Lebedev

Andrey V. Droblenkov

Sarng S. Pyurveev

Galina P. Kosyakova

Maria A. Netesa

Viktor A. Lebedev

INFLUENCE OF SOCIAL STRESS IN EARLY ONTOGENESIS ON THE MANIFESTATION OF BINDGE EATING AND GHRELIN CONTENT IN THE HYPOTHALAMUS OF RATS

早期个体发生中社会压力对大鼠下丘脑中暴食行为和胃饥饿素含量的影响

Background. The goal of pharmacokinetic (PK) studies of drugs is to increase the effectiveness of their use in clinical practice. The effect of psychotropic drugs may largely depend on the rate of their elimination from the body. The mechanisms of drug interactions between psychotropic drugs are associated with the processes of biotransformation of drugs by enzymes of microsomal oxidation of cytochromes P-450 in the liver. Various drugs can increase or decrease the activity of microsomal enzymes of the monooxidase cytochrome P450-dependent system (MOS), which can lead to a change in the effective level of drugs in the patient's body due to inhibition or stimulation of the induction of key liver enzymes. Purpose. To evaluate the effect of pharmacotherapy of psychotropic drugs: Alprazolam, Bromazepam, Lithium carbonate on the metabolic rate of the model AP substrate in saliva in patients with neuropsychiatric disorders; influence of the enzyme-inducing activity of the innovative anticonvulsant Galodif® on the PK parameters of AP in healthy volunteers. Materials and methods. The study was conducted in the department of borderline conditions of the Research Institute of Mental Health of the Tomsk National Research Medical Center of the Russian Academy of Sciences and included 34 male patients, the average age was 42.73 ± 4.39 years. The patients were divided into three groups according to the nosological forms of the disease according to ICD-10: Group 1 (12 people) - heading F43.23 “Adaptation disorder with a predominance of disturbance of other emotions” and F43.25 “Mixed disorder of emotions and behavior caused by disorder adaptation", 2nd group (12 people) - heading F06.61 "Organic emotionally labile disorder due to vascular disease of the brain", 3rd group (10 people) consisted of patients with a diagnosis of F41.2 according to ICD 10 "Mixed anxiety and depressive disorder." Patients in the 1st group were prescribed Alprazolam (0.5 - 1.5 mg/day) as the main therapy, in the 2nd group - Bromazepam (6 - 12 mg/day), in the 3rd group - Lithium carbonate (500 - 1000 mg/day). The course of therapy for patients in all 3 groups was 21 days. Patients of group 2 were additionally prescribed vascular therapy, nootropic drugs, and vitamin therapy. The comparison group consisted of 10 healthy volunteers, standardized by gender and age. The influence of the enzyme-inducing effect of the innovative anticonvulsant Galodif® (at a dose of 200 mg/day, course for 21 days) on the pharmacokinetic parameters of antipyrine (AP) was assessed in the saliva of volunteers, since patients were not prescribed Galodif® during therapy. Determination of the PK parameters of AP as a test witness of elimination processes from the body of patients and volunteers was carried out before the administration of the study drugs and at the end of the course of therapy. AP was prescribed to volunteers and patients at a dose of 10 mg/kg once on an empty stomach. Saliva samples were collected at 0.5; 1.0; 2.0; 3.0; 6.0; 12.0; 24.0 hours after taking the test medication. AP concentration was assessed spectrophotometrically. The AP content was calculated according to the graph using AP solutions of 0.5–100 μg/ml. Calculation of model-independent parameters of pharmacokinetics: half-life (T1\2,h), total clearance (CLt, ml/min), area under the pharmacokinetic curve (AUC, μg·min/ml) was carried out using the method of statistical moments as modified by V. Piotrovsky (1986). Statistical processing of the data was carried out using “Statistika 12.0” for “Windows” non-parametric Kolmogorov-Smirnov test. Samples were checked for normality of distribution using the Shapiro–Wilcoxon test. Differences were considered significant at p 0.05. Results. Use of Alprazolam as the main therapy by patients of group 1 at a dose of 0.5 - 1.5 mg/day, a course of 21 days, did not significantly affect the PK parameters of AP: half-life of AP (T½), total clearance (CLt), area under the pharmacokinetic curve (AUC). Alprazolam did not change the elimination of AP from the saliva of the studied patients - as an indicator of the state of oxidative metabolism of xenobiotics in the liver in patients. In patients of group 2 who received Bromazepam, there was a background reduction in the half-life of AP (T½), an increase in total clearance (CLt), and a decrease in the area under the pharmacokinetic curve - concentration-time (AUC), caused by vascular, nootropic and vitamin therapy. Comparison of the PK parameters of AP under the influence of a course of therapy with the prescription of Bromazepam in daily doses of 6–12 mg with background indicators did not reveal significant differences, which indicates accelerated elimination of AP in connection with concomitant therapy. Therapy with lithium carbonate at a dose of 500-1000 mg in patients of group 3 did not change the PK parameters of AP elimination. The data obtained indicate that the studied psychotropic drugs in the indicated dosages did not affect the activity of liver MOS in patients in all 3 groups. Study of the effect of Galodif® use on the PK parameters of AP in healthy volunteers revealed a diametrically opposite result: a significant decrease in half-life (T1/2) ≈ 2 times, an increase in total clearance (CLt), a reduction in the area under the pharmacokinetic curve (AUC), which indicates an accelerated elimination of AP from the saliva of the subjects and indicates the induction of MOS in the liver. Conclusion. Pharmacotherapy using the studied psychotropic drugs in patients in all 3 groups is not associated with induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. Galodif stimulated the induction of hepatic MOS in volunteers.

Tamara Shushpanova

Irina Е Kupriyanova

Nikolay Aleksandrovich Bokhan

INFLUENCE OF PHARMACOTHERAPY ON FUNCTION OF BIOTRANSFORMATION OF XENOBIOTICS LIVER IN PATIENTS WITH NEUROPSYCHIATRIC DISORDERS

药物治疗对神经精神障碍患者肝脏异生物代谢功能的影响

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Cyclotides. Prospects for using violet oxytocin-like substances to create a new generation of pharmacological agents

Prospects for the use of perampanel in the treatment of epilepsy in patients with malignant gliomas of the brain

Absorption, distribution, metabolism and excretion of carbon nanostructures

Hypoxic irreversible brain cells damage, associated risk factors and antihypoxants

EFFECTIVENESS OF THE COMBINATION OF METFORMIN AND INTRANASAL INSULIN FOR THE CORRECTION OF METABOLIC AND HORMONAL DISTURBANCES IN ADULT MALE RATS WITH METABOLIC SYNDROME INDUCED BY IMPAIRED BREASTFEEDING

Cyclotides. Prospects for using violet oxytocin-like substances to create a new generation of pharmacological agents

Modern Russian drugs for the treatment of neurodegenerative diseases

The preliminary introduction of hydrogen peroxide into the stomach of aquarium fish increases their survival rate in conditions of acute hypoxia

INFLUENCE OF SOCIAL STRESS IN EARLY ONTOGENESIS ON THE MANIFESTATION OF BINDGE EATING AND GHRELIN CONTENT IN THE HYPOTHALAMUS OF RATS

INFLUENCE OF PHARMACOTHERAPY ON FUNCTION OF BIOTRANSFORMATION OF XENOBIOTICS LIVER IN PATIENTS WITH NEUROPSYCHIATRIC DISORDERS

ISSN	1683-4100, 2542-1875
h-index	5