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Vol 21, No 4 (2023)

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Reviews

Pyolytics as a product of the physical–chemical repurposing of antiseptics and an alternative to larval therapy for chronic wounds

Urakov A.L., Urakova N.A., Reshetnikov A.P., Shabanov P.D., Wang Y., Bodduluri P.V., Samorodov A.V., Rozov R.A., Shchemeleva A.A., Novikov V.E., Pozhilova E.V.

Abstract

The traditional treatment of chronic wounds involves daily cleansing of the wound surface from purulent necrotic masses using mechanical and medicinal methods, accompanied by regular replacement of wound dressing. In this case, medicinal wound cleansing lasts 10–15 mins from the time of replacement of the old wound dressing with the new one. According to established practice, medicinal sanitation of infected and purulent wounds during dressing involves irrigation of the wound surface with cleansing solutions, antiseptics, and/or antibiotics. In severe cases, the above therapy is supplemented with live larvae of the necrophage fly, which are injected into purulent necrotic masses and left in them under wound dressing until wounds are completely cleansed from pus. Nevertheless, the generally accepted course of treatment of chronic wounds remains ineffective. The use of pyolytics and their supplementation with wound dressings in the form of warm wet compresses, which create a local greenhouse effect in wounds, was reported to accelerate the healing of chronic wounds. Pyolytics are a group of antiseptics developed in Russia. They are warm alkaline solutions of hydrogen peroxide; when they interact with purulent necrotic masses, these solutions dissolve very quickly and foam them. Because of the interaction with pyolytics, thick purulent masses immediately turn into fluffy oxygenated foam. Pyolytics have been developed because of the physicochemical repurposing of aqueous solutions of sodium hydrogen carbonate and hydrogen peroxide. To accelerate the healing of chronic wounds, a recommendation was to irrigate the surface of chronic wounds with 3% hydrogen peroxide and 2–10% sodium bicarbonate solutions, heated to 37–45°C, which have alkaline activity at pH 8.4–8.5 and are enriched with dissolved carbon dioxide or oxygen (due to excess pressure of 0.2 atm). This study presented the importance of treating chronic wounds using politics and treatment outcomes using pyolytics along with warm moist dressing compresses, demonstrating a wound-healing effect. Consequently, physical and chemical reprofiling of antiseptics may make them effective pyolytics, and the combination of pyolytics with warm wound dressings such as warm moist compresses, which create a local greenhouse effect on wounds, accelerates the healing of chronic wounds.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):287-297
pages 287-297 views

Bacteriophages: Clinical significance and application prospects

Danilov A.I., Evseev A.V.

Abstract

A review of the literature data covering topical issues of the use of bacteriophages in clinical practice is presented. Traditionally, phage therapy is based on the use of natural phages for the lysis of bacteria at the infection site. Despite some limitations, it has significant advantages over antibiotic therapy. The use of biotechnological methods currently makes it possible to eliminate the disadvantages of phage therapy by creating recombinant drugs and, in the future, expand its capabilities through the use of lytic phage proteins and their modified derivatives. Currently, bacteriophages are used not only for the treatment of infections but also for prevention and diagnosis (phagotyping to identify the source of infection). Bacteriophages are also used in genetic engineering as vectors for transferring DNA sections. Few side effects have been described about bacteriophages. Particularly, they do not negatively affect the intestinal microbiota, and compared with antibiotics, they are much less likely to be associated with allergic reactions. Moreover, existing randomized clinical trials, which are the gold standard of clinical trials, in phage therapy are extremely insufficient, which dictates the need to concentrate the efforts of all stakeholders in this direction.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):299-305
pages 299-305 views

Prospects for the pharmacological validation of the use of platelets as a “peripheral model” of neurons

Urakov A.L., Nikitina I.L., Klen E.E., Wang Y., Samorodov A.V.

Abstract

Depressive disorders often occur in patients with cardiovascular pathologies and are a predictor of the development of thrombotic events, such as myocardial infarction, acute ischemic cerebrovascular accident, and pulmonary embolism. These are believed to be caused by the structural and biochemical relationship between platelets and brain neurons, which allows us to consider platelets as a marker of central nervous system (CNS) pathologies. This review aimed to assess the relationship between the hemostasis system and the development of depressive disorders using platelets as a “peripheral model” of neurons and evaluate the effectiveness of drugs for the treatment of depression. The study was conducted in accordance with the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature search was conducted using PubMed, Cochrane, and CINAHL databases from 2018 to 2023, according to the following keywords: “hemostasis,” “acute cerebrovascular accident,” “depression,” “depressive disorders,” “platelets,” “cardiovascular diseases.” The data obtained indicate both a clinical link between depressive disorders and vascular events and the commonality of platelets and CNS cells because of the commonality of the following proteins: transporters and receptors of serotonin or 5-hydroxytryptamine, amyloid precursor protein, and brain neurotrophic factor, which were previously considered specific neural proteins. In addition, a relationship exists between hemostasis dynamics and drug therapy for depression. In this review, changes in hemostasis in terms of platelet activation in patients with depression and vascular disease were critically analyzed. The literature presents diverse mechanisms of platelet induction, which require further study. A rational study of the pathways of platelet activation in patients with depressive disorders will provide a comprehensive understanding of the molecular mechanisms underlying the relationship between hemostasis and depression in various vascular pathologies. Platelet activation in patients with depression and the dynamics of changes in hemostasis parameters during the treatment of depressive disorders allow us to consider hemostasis as a peripheral marker of the CNS and pharmacotherapy.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):307-317
pages 307-317 views

Idealization in pharmacology and pharmacy: Symbol of the chemical formula of one molecule of a substance and a real pharmaceutical product

Urakov A.L., Shabanov P.D.

Abstract

The essence of the two levels of information used in modern pharmacy, pharmacology, and medicine for operations related to theoretical reasoning about medicines and the actual practice of their use for treating specific cases is fundamentally different. In particular, studies have analyzed the essence of theoretical information about medicines and the norms of their use in accordance with medical care standards. Information about medicines and standards of medical care, which dominate textbooks, reference books, encyclopedias, scientific articles , and normative and technical documents, is built on the idealized essence of chemically pure substances and their interaction with an idealized virtual patient. Accordingly, in the fields of pharmacy, pharmacology, and chemistry, physics, and materials science, researchers have traditionally represented chemical elements (and drugs) by certain chemical formulas, names, and symbols for their molecules. Moreover, in pharmacy and pharmacology, the structural formula of one molecule of only one chemical substance belonging to the group of the so-called main active substances most often plays this role. Generally, this chemical symbol of its molecule is identified with the real substance itself. It is assumed that the substance in question is of ideal high quality, is completely free of any impurities, is not combined with other substances, and does not represent a certain pharmaceutical product (it is not a tablet, not a solution, not an ointment, not an aerosol, etc.), and is not manufactured by a certain pharmaceutical company according to a certain recipe. Moreover, modern pharmaceutical products are not separate molecules, not pure chemical reagents, but all sorts of mixtures of different substances of different quality in different ratios. In addition, each pharmaceutical product of each manufacturing plant and each series number has inherent and unique mechanical, physical, chemical, and physicochemical properties and quality indicators. Therefore, the idealized essence of drugs is far from that of real pharmaceutical products. The chemical name and chemical formula are symbols of one molecule of a chemical element, reflecting its idealized chemical essence, but not the essence of a real “tablet”, “ampule”, and/or “tube” with it. In turn, the virtual patient of known sex, average age, average health status, and a body weight of approximately 70 kg implied by the standards of medical care is just an idealized object of interaction with an idealized “medicine”. In this regard, the study of the relationship between the idealized and real drugs and patients is a crucial part of the problem of the relationship between theory and reality in pharmacy, pharmacology, and medicine.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):319-327
pages 319-327 views

Original articles

Psychic trauma causes increased impulsivity in a model of gambling addiction by altering dopamine and serotonin metabolism in the prefrontal cortex

Pyurveev S.S., Lebedev A.A., Tsikunov S.G., Karpova I.V., Bychkov E.R., Shabanov P.D.

Abstract

BACKGROUND: Gambling addiction (gambling) involves frequently repeated episodes of gambling that are detrimental to social, professional, material, and family values. Gambling addiction is often combined with posttraumatic stress disorder.

AIM: This study aimed to examine the effect of predator presentation stress on the manifestations of gambling addiction in an animal model in a test of probability and magnitude of reinforcement in the Iowa gambling task and monoamine metabolism in the prefrontal cortex of rats.

MATERIALS AND METHODS: Rats were trained in a test of probability and magnitude of reinforcement in the Iowa gambling task in a 3-beam maze. Each run in arm 1 of the maze was reinforced with one sunflower seed, each second run in arm 2 with two seeds, and each third run in arm 3 with three seeds. Correspondingly, half of the runs in arm 2 and 2/3 of the runs in arm 3 were left unreinforced. After training, the animals were placed in a terrarium with a tiger python, one of which was victimized for its food requirements. On day 14 after predator presentation, dopamine and serotonin metabolism in the prefrontal cortex was determined using high-performance liquid chromatography with electrochemical detection.

RESULTS: The levels of the dopamine metabolite dioxyphenylacetic acid and the ratio of dioxyphenylacetic acid to dopamine in the prefrontal cortex decreased. The levels of serotonin, its metabolite 5-hydroxyindoleacetic acid, and the ratio of 5-hydroxyindoleacetic acid to serotonin in the prefrontal cortex were also decreased in rats after exposure to a predator. Moreover, predator presentation induced significant behavioral changes in rats, increasing impulsivity in making choices in a test of probability and magnitude of reinforcement in the Iowa gambling task. The acute vital stress of predator presentation increased the number of escapes to arm 3 of the maze, suggesting that the animals exhibited more risky behavior when choosing reinforcements of different strengths and probability.

CONCLUSIONS: The animal model showed that the depletion of the dopaminergic and serotoninergic systems of the prefrontal cortex underlies pathological gambling addiction and inadequate decision-making caused by posttraumatic stress disorder.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):329-338
pages 329-338 views

A new ghrelin receptor antagonist, agrelax, reduces emotional overeating caused by the stimulation of the lateral hypothalamus reward zone in well-fed rats

Lebedev A.A., Bychkov E.R., Lukashkova V.V., Lebedev V.A., Efimov N.S., Shabanov P.D.

Abstract

BACKGROUND: Ghrelin receptor antagonists hold promise for the treatment of eating disorders. The reward zone of the lateral hypothalamus has been proposed as a target for mediating the effects of the ghrelin system in emotional overeating.

AIM: This study aimed to evaluate the effects of a new ghrelin receptor antagonist, agrelax, on emotional overeating induced by the stimulation of the reward zone of the lateral hypothalamus in well-fed rats.

MATERIALS AND METHODS: Male Wistar rats were trained to self-stimulate in a Skinner box. After training, a feeder was placed in the Skinner box, and a food-conditioned reflex was developed in the rats for 5 days. Then, the reaction of food self-deprivation, i.e., behavior under conditions of choice of self-stimulation or food intake, was assessed.

RESULTS: The reaction of food self-deprivation when the animals did not approach the feeder was >10% of the threshold current. Self-stimulation of the lateral hypothalamus with a threshold current caused numerous approaches to the feeder and food intake. Sulpiride, a dopamine D2/D3 antagonist (5 and 20 mg/kg ip), administered to well-fed rats reduced both feeding behavior and the intensity of self-stimulation in the food self-deprivation test at threshold currents. The ghrelin receptor antagonists [D-LYS3]-GHRP-6 and the novel antagonist agrelax (1 µg/µL, 20 µL intranasally) also reduced both feeding behavior and the intensity of self-stimulation under these conditions.

CONCLUSIONS: Ghrelin and dopamine receptors are involved in emotional overeating. Agrelax, a novel ghrelin receptor antagonist, reduces emotional overeating induced by the activation of the lateral hypothalamic reward system. Because emotional overeating is strongly associated with clinical eating disorders such as bulimia and binge-eating disorder, the use of ghrelin antagonists to treat and prevent this problem is promising.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):339-348
pages 339-348 views

Effect of new coumarin derivatives on the impulsive and compulsive components of gambling addiction in rats

Daliev B.B., Lebedev A.A., Bychkov E.R., Shabanov P.D.

Abstract

BACKGROUND: The search for new neuroactive compounds that selectively affect the mechanisms of emotional reinforcement in gambling addiction is of interest. No previous studies have examined the effects of coumarins on gambling addiction.

AIM: This study aimed to investigate the effect of new coumarin derivatives on the impulsive and compulsive components of gambling addiction in rats.

MATERIALS AND METHODS: The effects of drugs on elements of gambling addiction were assessed in rats in the “marble burying” test and “probability and magnitude of reinforcement” in the three-arm maze, a version of the Iowa test. The effects of the following six coumarin derivatives were assessed: LVM-091, LVM-092, LVM-096, LVM-099, LVM-S144, and IEM-2886.

RESULTS: In the “burrowing balls” test, substances synthesized based on coumarins LVM-092, LVM-099, LVM-S144, and IEM-2886 reduced the level of compulsivity, reducing the number of buried balls compared with the control and diazepam groups (p ≤ 0.05). In the “probability and magnitude of reinforcement” test, after the administration of drugs LVM-091, LVM-099, LVM-S144, and IEM-2886, the level of impulsivity and risk behavior decreased, reducing the number of animals entering the sleeve with the greatest reinforcement and its low probability.

CONCLUSIONS: New coumarin derivatives cause an anticompulsive effect and reduce the impulsivity level in rats, which in the future can be used for treating obsessive–compulsive disorders and addictive conditions, such as Internet addiction and gaming addiction.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):349-356
pages 349-356 views

Tissue oxidative metabolism and microhemodynamics of the skin in rats exposed to stress factors of different durations and combinations

Ravaeva M.Y., Cheretaev I.V., Chuyan E.N., Galenko-Yaroshevskii P.A., Dzheldubaeva E.R., Mironyuk I.S.

Abstract

BACKGROUND: Changes in tissue oxidative metabolism under the action of stressors of different durations have not been studied. The relationship between NADH and FAD coenzymes and the microcirculatory bed remains unclear.

AIM: This study aimed to identify the features of the reaction of skin microhemodynamics and tissue oxidative metabolism in rats exposed to acute and chronic stress factors of different durations and their combinations.

MATERIALS AND METHODS: The experiment was performed on 100 male Wistar rats weighing 200–220 g. The animals were divided into five groups of 20 rats. The first control group and the second and third groups were exposed to acute stress (AS) and chronic hypokinetic stress (HS), respectively; the fourth group (AS-HS) was previously exposed to AS (on the first day) and then to HS (1–10 days); and the fifth group (for 10 days of the HS, then the effect of the AS on day 10). On day 10, the indicators of tissue oxidative metabolism and skin microhemodynamics were recorded.

RESULTS: AS and HS increased the requirement of cells for ATP and contributed to the predominance of oxidative phosphorylation over other processes, as indicated by an increase in FAD. AS-HS significantly changed oxidative metabolism, separating oxidative phosphorylation and activating glycolysis. HS-AS did not cause such changes. AS increased the microcirculation index and reduced the coefficient of variation, and HS reduced the microcirculation index and increased the mean square deviation. AS–HS significantly increased the microcirculation index, and HS-AS increased the mean square deviation and coefficient of variation but reduced the microcirculation index.

CONCLUSIONS: AS and HS increase the requirement of cells for ATP and contribute to the predominance of oxidative phosphorylation over other processes. AS-HS modifies oxidative metabolism by disconnecting oxidative phosphorylation and activating glycolysis. HS-AS depletes the metabolic reserves of the body. AS-HS rearranges metabolism along the path of glycolysis, protecting against stress factors and preventing the development of oxidative stress. AS leads to hyperemia and stasis of blood circulation in the microarray, reducing the vasomotor activity of the vessels. HS inhibits the level of tissue perfusion and reduces the inflow of arterial blood into the microcirculatory bed and the outflow of venous blood, leading to spastic, stagnant phenomena and stasis. AS-HS reduces vasoconstriction, preparing a microcirculatory bed for prolonged hypokinesia. HS-AS levels vasodilation and improves the parameters of skin microhemodynamics (mean square deviation and coefficient of variation).

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):357-366
pages 357-366 views

Influence of new dimethylaminoethanol derivatives, butanoic and trans-butenedioic acids, on the tolerability of hypoxia, hyperthermia, and hypothermia

Kim A.E., Shustov E.B.

Abstract

BACKGROUND: The need to increase the tolerance of various extreme effects is associated not only with the expansion of human professional activity regions but also with the need to assist victims of natural and man-made disasters. The use of pharmacological agents for individual adverse effects is a well-known method; however, considering the combined effects of several physical or chemical factors, only a few references are found in the literature.

AIM: This preclinical study aimed to examine the effectiveness of a new derivative of aminoethanol and intermediates of the Krebs cycle in relation to the isolated and combined effects of hypoxia and temperature (hyperthermia and hypothermia).

MATERIALS AND METHODS: The fumaric salt of the amber ether of diethylaminoethanol was synthesized at St. Petersburg State University of Chemistry and Pharmacy, Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was conducted on small laboratory animals. Resistance to hypoxia was assessed by the dynamics of the altitude threshold of animals, tolerance to hyperthermia by survival in a thermal chamber at 40°C, and tolerance to hypothermia by the time of maximum swimming in water at 10–12°C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was induced by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, and thermal exposure was induced by placing the animal in water at 40°C (hyperthermia) or 9–11°C (hypothermia).

RESULTS: After a single intragastric administration in a wide range of doses, the test compound stimulated the physical performance of animals and exhibited a protective effect under the isolated effects of hypobaric hypoxia, hyperthermia, and hypothermia. With combined exposure to hemic hypoxia and hyperthermia, the compound was effective at a dose of 250 mg/kg. With combined exposure to hemic hypoxia and hypothermia, efficiency was also noted at lower doses (25 and 50 mg/kg).

CONCLUSION: Fumaric salt of dimethylaminoethanol amber ether, a new derivative of dimethylaminoethanol, butenedioic, and trans-butenedioic acids, is promising for further study as a means of increasing the body’s resistance to extreme influences.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):367-372
pages 367-372 views

The effectiveness of the original anticonvulsant Galodif® — a GABAA receptor modulator for alcohol withdrawal syndrome

Shushpanova T.V., Mandel A.I., Bokhan N.A., Schastnyy E.D.

Abstract

BACKGROUND: The development of new drugs to improve the effectiveness of treatment and rehabilitation programs for patients suffering from addiction diseases, which are non-addictive and have a stimulating effect on detoxification processes in the body, can increase the effectiveness of therapy and reduce the cost of treatment. A deficiency of GABAergic inhibition in brain structures plays a leading role in the occurrence of paroxysmalness. The innovative anticonvulsant Galodif® (1-[(3-chlorophenyl)(phenyl)methyl]urea), a GABAA receptor modulator, has low toxicity and hepatoprotective properties, which allows it to be recommended for use in the treatment of patients with alcohol dependence.

AIM: The aim of this study is to evaluation of the effectiveness of the use of the anticonvulsant drug galodif1 in complex therapy in patients with alcohol dependence with compulsive and paroxysmal disorders with pathological craving for alcohol when withdrawing of alcohol.

MATERIALS AND METHODS: A limited open-type clinical study of the therapeutic effectiveness of the innovative anticonvulsant galodif1 included 128 male patients (average age 38.3 ± 8.9 years) with a diagnosis of “Mental and behavioral disorders as a result of alcohol consumption, dependence syndrome” (F10.232) and “Mental and behavioral disorders as a result of alcohol consumption, withdrawal states” (F10.302). 68 patients received Galodif® 300 mg per day as an anticonvulsant for 21 days. 60 patients made up the comparison group, receiving carbamazepine at a dose of 400 mg per day.

RESULTS: The use of the anticonvulsant Galodif® in complex therapy of patients revealed: normothymoleptic activity of the drug; when assessing depression on the Hamilton Depression Rating Scale (HDRS), the average total score decreased from 28.3 ± 1.3 to 5.7 ± 1.9, and a reduction in unmotivated fear and anxiety was noted; vegetative stabilizing effect with a sympathicolytic component with normalization of heart rate; reduction of headaches; weakening or disappearance of pathological desire during withdrawal syndrome in 88% of cases, in the post-withdrawal state — in 57% of cases; taking the drug did not cause any unwanted side effects.

CONCLUSIONS: The use of the anticonvulsant Galodif®, which modulates GABAA receptors, has low toxicity and detoxification properties and does not cause side effects, has been proposed as one of the modern pharmacotherapeutic approaches in the treatment of patients with alcohol dependence.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(4):373-389
pages 373-389 views


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