Introduction. The need to increase the tolerance of various extreme impacts is associated not only with the expansion of the regions of human professional activity, but also with the need to provide assistance to victims in the centers of natural disasters and man-made disasters. The use of pharmacological agents for this purpose for individual adverse effects is a well-known method, however, with regard to the combined effect of several physical or chemical factors, only a few references are found in the literature. In this regard, the purpose of this work was a preclinical study of 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 the temperature factor (hyperthermia and hypothermia). Materials and methods. The compound under study was synthesized at the Department of Organic Chemistry at the Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was performed 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 a temperature of +40 C, tolerance to hypothermia - by the time of maximum swimming in water with a temperature of 10-12 C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was created by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, thermal exposure - by placing the animal in water with a temperature of 40 C (hyperthermia) or 9-11 C (hypothermia). Results. The test compound after a single intragastric administration in a wide range of doses stimulates the physical performance of animals and exhibits 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, 50 mg/kg). Conclusion. A new derivative of dimethylaminoethanol, butanedioic and trans-butenedioic acids is promising for further study as a means of increasing the body's resistance to extreme effects.
导言。提高对各种极端影响的耐受力不仅与人类职业活动区域的扩大有关，还与向自然灾害和人为灾害中心的受害者提供援助的需要有关。为此，针对个别不利影响使用药理制剂是一种众所周知的方法，但对于多种物理或化学因素的综合影响，文献中仅有少数参考文献。在这方面，这项工作的目的是对一种新的氨基乙醇衍生物和克雷布斯循环中间体对缺氧和温度因素（高热和低温）的单独和综合影响的有效性进行临床前研究。材料和方法。所研究的化合物是在有机化学系（系主任 I.P. Yakovlev 教授）合成的。研究在小型实验动物身上进行。对缺氧的抵抗力通过动物的海拔阈值动态来评估，对高热的耐受力--通过在温度为 +40 C 的热室中的存活率来评估，对低温的耐受力--通过在温度为 10-12 C 的水中的最大游泳时间来评估。在综合暴露条件下，动物的状况通过体能表现的动态变化来评估；缺氧是通过初步服用剂量为 50 毫克/千克的高铁血红蛋白前亚硝酸钠来制造的；热暴露--将动物置于温度为 40 摄氏度（高热）或 9-11 摄氏度（低体温）的水中。结果单次胃内给药后，试验化合物在不同剂量范围内都能刺激动物的体能表现，并在低压缺氧、高热和低体温的单独作用下显示出保护作用。联合暴露于血液缺氧和高热时，该化合物在 250 毫克/千克的剂量下有效；联合暴露于血液缺氧和低体温时，在较低剂量（25、50 毫克/千克）下也有效。结论二甲基氨基乙醇、丁二酸和反式丁二酸的一种新衍生物有望作为增强机体对极端效应抵抗力的一种手段得到进一步研究。
{"title":"Preclinical study of the influence of a new dimethylaminoethanol derivative, butandioic and trans-butenedioic acids on the tolerability of hypoxia, hyperthermia and hypothermia","authors":"A. E. Kim, Evgeny B. Shustov","doi":"10.17816/rcf568686","DOIUrl":"https://doi.org/10.17816/rcf568686","url":null,"abstract":"Introduction. The need to increase the tolerance of various extreme impacts is associated not only with the expansion of the regions of human professional activity, but also with the need to provide assistance to victims in the centers of natural disasters and man-made disasters. The use of pharmacological agents for this purpose for individual adverse effects is a well-known method, however, with regard to the combined effect of several physical or chemical factors, only a few references are found in the literature. In this regard, the purpose of this work was a preclinical study of 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 the temperature factor (hyperthermia and hypothermia). Materials and methods. The compound under study was synthesized at the Department of Organic Chemistry at the Department of Organic Chemistry (Head Professor I.P. Yakovlev). The study was performed 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 a temperature of +40 C, tolerance to hypothermia - by the time of maximum swimming in water with a temperature of 10-12 C. Under combined exposure, the condition of the animals was assessed by the dynamics of physical performance, hypoxia was created by preliminary administration of the methemoglobin former sodium nitrite at a dose of 50 mg/kg, thermal exposure - by placing the animal in water with a temperature of 40 C (hyperthermia) or 9-11 C (hypothermia). Results. The test compound after a single intragastric administration in a wide range of doses stimulates the physical performance of animals and exhibits 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, 50 mg/kg). Conclusion. A new derivative of dimethylaminoethanol, butanedioic and trans-butenedioic acids is promising for further study as a means of increasing the body's resistance to extreme effects.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"47 58","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139203989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander L. Urakov, I. L. Nikitina, E. E. Klen, Yi Wang, A. Samorodov
Introduction. Depressive disorders are often found in patients with pathology of the cardiovascular system and are a predictor of the development of thrombotic events, such as myocardial infarction, acute ischemic cerebrovascular accident, pulmonary embolism. There are reasons to believe that this is due to the structural and biochemical relationship of platelets and brain neurons, which allows us to consider platelets as a marker of the pathology of the central nervous system. The purpose of this review is to assess the relationship between the hemostasis system and the development of depressive disorders from the standpoint of using platelets as a peripheral model of neurons and evaluating the effectiveness of drugs for the treatment of depression. Materials and methods. The work was carried out in accordance with the recommendations of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). For this review, a systematic literature search was conducted using PubMed, Cochrane and CINAHL databases for the period from 2018 to 2023, according to the keywords, hemostasis, acute cerebrovascular accident, depression, depressive disorders, platelets, cardiovascular diseases". Results. The data obtained indicate both a clinical link between depressive disorders and vascular events, and the commonality of platelets and CNS cells due to the commonality of the following proteins: transporters and receptors of serotonin or 5-hydroxytryptamine (5-HT), amyloid precursor protein (APP) and brain neurotrophic factor (BDNF), which previously they were considered specific neural proteins. In addition, there is a relationship between the dynamics of hemostasis and drug therapy for depression. Conclusions. In this review, we critically analyzed changes in hemostasis in terms of platelet activation in depressed patients with vascular disease. The mechanisms of platelet induction presented in the literature are diverse and require further study. A rational study of the pathways of platelet activation in patients with depressive disorders will provide a comprehensive understanding of the essence of the molecular mechanisms underlying the relationship of hemostasis in patients with depression in various vascular pathologies. Platelet activation in patients with depression and the dynamics of changes in hemostasis system parameters during the treatment of depressive disorders allows us to consider hemostasis as a peripheral marker of the central nervous system and pharmacotherapy.
{"title":"Prospects for pharmacological validation of the use of platelets as a \"peripheral model\" of neurons","authors":"Alexander L. Urakov, I. L. Nikitina, E. E. Klen, Yi Wang, A. Samorodov","doi":"10.17816/rcf568907","DOIUrl":"https://doi.org/10.17816/rcf568907","url":null,"abstract":"Introduction. Depressive disorders are often found in patients with pathology of the cardiovascular system and are a predictor of the development of thrombotic events, such as myocardial infarction, acute ischemic cerebrovascular accident, pulmonary embolism. There are reasons to believe that this is due to the structural and biochemical relationship of platelets and brain neurons, which allows us to consider platelets as a marker of the pathology of the central nervous system. The purpose of this review is to assess the relationship between the hemostasis system and the development of depressive disorders from the standpoint of using platelets as a peripheral model of neurons and evaluating the effectiveness of drugs for the treatment of depression. Materials and methods. The work was carried out in accordance with the recommendations of Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). For this review, a systematic literature search was conducted using PubMed, Cochrane and CINAHL databases for the period from 2018 to 2023, according to the keywords, hemostasis, acute cerebrovascular accident, depression, depressive disorders, platelets, cardiovascular diseases\". Results. The data obtained indicate both a clinical link between depressive disorders and vascular events, and the commonality of platelets and CNS cells due to the commonality of the following proteins: transporters and receptors of serotonin or 5-hydroxytryptamine (5-HT), amyloid precursor protein (APP) and brain neurotrophic factor (BDNF), which previously they were considered specific neural proteins. In addition, there is a relationship between the dynamics of hemostasis and drug therapy for depression. Conclusions. In this review, we critically analyzed changes in hemostasis in terms of platelet activation in depressed patients with vascular disease. The mechanisms of platelet induction presented in the literature are diverse and require further study. A rational study of the pathways of platelet activation in patients with depressive disorders will provide a comprehensive understanding of the essence of the molecular mechanisms underlying the relationship of hemostasis in patients with depression in various vascular pathologies. Platelet activation in patients with depression and the dynamics of changes in hemostasis system parameters during the treatment of depressive disorders allows us to consider hemostasis as a peripheral marker of the central nervous system and pharmacotherapy.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"15 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139205621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ravaeva, I. Cheretaev, Elena N. Chuyan, Pavel A. Galenko-Yaroshevskii, E. R. Dzheldubayeva, I. Mironyuk
BACKGROUND: Changes in tissue oxidative metabolism (OM) under the action of stressors of different duration have not been studied. The question of the relationship of NADH and FAD coenzymes with the microcirculatory bed (MCB) remains open. AIM: The work is devoted to identifying the features of the reaction of skin microhemodynamics (MHS) and tissue OM in rats exposed to acute and chronic stress factors of different duration and their combinations. MATERIALS AND METHODS: The experiment was carried out on 100 male rats of the Wistar line weighing 200-220 g. The animals were divided into 5 groups of 20 rats. The 1st control group, the 2nd and 3rd groups were exposed to acute (AS) and chronic hypokinetic stress (HS), respectively; the 4th group (AS-HS) was previously exposed to AS (on the 1st day), and then to HS (1-10 days); 5-th group (for 10 days of the HS, then the impact of the AS on the 10th day). On the 10th day, the indicators of tissue OM and MHS were recorded. RESULTS: It was shown that AS and HS increase the requirement of cells for ATP and contribute to the predominance of oxidative phosphorylation (OPh) over other processes, as indicated by an increase in FAD. AS-HS significantly changes the OM, separating the OPh and activating glycolysis. HS-AS does not cause such changes. AS increases the microcirculation index (MI) and reduces the coefficient of variation (Cv), HS reduces the MI and increases the mean square deviation (MSD). AS-HS significantly increases MI, and HS-AS MSD and Cv, but reduces MI. CONCLUSIONS: AS and HS increase the requirement of cells for ATP and contribute to the predominance of OPh over other processes. AS-HS modifies OM, disconnecting OPh 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 vasomotor activity of vessels. HS inhibits the level of tissue perfusion, reduces the inflow of arterial blood into the MCB and the outflow of venous blood, leading to spastic, stagnant phenomena and stasis. AS-HS reduces vasoconstriction, preparing the MCB for prolonged hypokinesia. HS-AS levels vasodilation, improves the parameters of MHS (MSD and Cv).
{"title":"Tissue oxidative metabolism and microhemodynamics of the skin in rats exposed to stress factors of different duration and their combinations","authors":"M. Ravaeva, I. Cheretaev, Elena N. Chuyan, Pavel A. Galenko-Yaroshevskii, E. R. Dzheldubayeva, I. Mironyuk","doi":"10.17816/rcf609553","DOIUrl":"https://doi.org/10.17816/rcf609553","url":null,"abstract":"BACKGROUND: Changes in tissue oxidative metabolism (OM) under the action of stressors of different duration have not been studied. The question of the relationship of NADH and FAD coenzymes with the microcirculatory bed (MCB) remains open. AIM: The work is devoted to identifying the features of the reaction of skin microhemodynamics (MHS) and tissue OM in rats exposed to acute and chronic stress factors of different duration and their combinations. MATERIALS AND METHODS: The experiment was carried out on 100 male rats of the Wistar line weighing 200-220 g. The animals were divided into 5 groups of 20 rats. The 1st control group, the 2nd and 3rd groups were exposed to acute (AS) and chronic hypokinetic stress (HS), respectively; the 4th group (AS-HS) was previously exposed to AS (on the 1st day), and then to HS (1-10 days); 5-th group (for 10 days of the HS, then the impact of the AS on the 10th day). On the 10th day, the indicators of tissue OM and MHS were recorded. RESULTS: It was shown that AS and HS increase the requirement of cells for ATP and contribute to the predominance of oxidative phosphorylation (OPh) over other processes, as indicated by an increase in FAD. AS-HS significantly changes the OM, separating the OPh and activating glycolysis. HS-AS does not cause such changes. AS increases the microcirculation index (MI) and reduces the coefficient of variation (Cv), HS reduces the MI and increases the mean square deviation (MSD). AS-HS significantly increases MI, and HS-AS MSD and Cv, but reduces MI. CONCLUSIONS: AS and HS increase the requirement of cells for ATP and contribute to the predominance of OPh over other processes. AS-HS modifies OM, disconnecting OPh 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 vasomotor activity of vessels. HS inhibits the level of tissue perfusion, reduces the inflow of arterial blood into the MCB and the outflow of venous blood, leading to spastic, stagnant phenomena and stasis. AS-HS reduces vasoconstriction, preparing the MCB for prolonged hypokinesia. HS-AS levels vasodilation, improves the parameters of MHS (MSD and Cv).","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139198908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The fundamentally different essence of 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 in the treatment of specific patients is reported. In particular, the essence of theoretical information about medicines and norms of their use in accordance with the standards of medical care is analyzed. It is shown that the information about medicines and standards of medical care, dominating nowadays in textbooks, reference books, encyclopedias, scientific articles and normative and technical documents, is built on the idealized essence of chemically pure substances and idealized essence of their interaction with an idealized virtual patient. In this regard, in the fields of pharmacy, pharmacology, and chemistry, physics, and materials science, researchers to date 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 so-called main active substances most often plays this role. As a rule, 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, it is completely free of any impurities, it 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. At the same time, 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. At the same time, each pharmaceutical product of each manufacturing plant and each series number has only inherent and unique mechanical, physical, chemical, physico-chemical properties and quality indicators. Therefore, the idealized essence of drugs is far from the essence of real pharmaceutical products. The chemical name and chemical formula are just a symbol of one molecule of a chemical element, reflecting its idealized chemical essence, but not the essence of a real "tablet", "ampoule" and/or "tube" with it. In turn, the virtual patient of average gender, average age, average health status, with a body weight of about 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 essence of drugs and patients is a crucial part of the problem of the relationship between theory and reality in pharmacy, pharmacology and in medicine.
{"title":"Idealization in pharmacology and pharmacy: Symbol of the chemical formula of a one molecule of a substance and real pharmaceutical product","authors":"Alexander L. Urakov, P. Shabanov","doi":"10.17816/rcf593274","DOIUrl":"https://doi.org/10.17816/rcf593274","url":null,"abstract":"The fundamentally different essence of 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 in the treatment of specific patients is reported. In particular, the essence of theoretical information about medicines and norms of their use in accordance with the standards of medical care is analyzed. It is shown that the information about medicines and standards of medical care, dominating nowadays in textbooks, reference books, encyclopedias, scientific articles and normative and technical documents, is built on the idealized essence of chemically pure substances and idealized essence of their interaction with an idealized virtual patient. In this regard, in the fields of pharmacy, pharmacology, and chemistry, physics, and materials science, researchers to date 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 so-called main active substances most often plays this role. As a rule, 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, it is completely free of any impurities, it 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. At the same time, 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. At the same time, each pharmaceutical product of each manufacturing plant and each series number has only inherent and unique mechanical, physical, chemical, physico-chemical properties and quality indicators. Therefore, the idealized essence of drugs is far from the essence of real pharmaceutical products. The chemical name and chemical formula are just a symbol of one molecule of a chemical element, reflecting its idealized chemical essence, but not the essence of a real \"tablet\", \"ampoule\" and/or \"tube\" with it. In turn, the virtual patient of average gender, average age, average health status, with a body weight of about 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 essence of drugs and patients is a crucial part of the problem of the relationship between theory and reality in pharmacy, pharmacology and in medicine.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139199753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrey А. Lebedev, Evgenii Bychkov, Viktoria Lukaskova, Viktor Lebedev, N. Efimov, Petr Shabanov
Relevance. Ghrelin receptor antagonists hold promise for the treatment of eating disorders. The reward zone of the lateral hypothalamus has been proposed as a target mediating the effects of the ghrelin system in emotional overeating. The aim was to study the effects of a new ghrelin receptor antagonist agrelax on emotional overeating induced by stimulation of the reward zone of the lateral hypothalamus in well-fed rats. Materials and methods. Male Wistar rats were trained self-stimulation in a Skinner box. After training, a feeder was placed in the Skinner box and a food conditioned reflex was developed in rats for 5 days. Next, we studied the reaction of food self-deprivation, i.e. behavior under conditions of choice of self-stimulation or food intake. Results. The reaction of food self-deprivation, when the animals did not approach the feeder, was observed at a value more than 10% of threshold current. Self-stimulation of the lateral hypothalamus with 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 intensity of self-stimulation in the food self-deprivation test at thresholds current. The ghrelin receptor antagonists [D-LYS3]-GHRP-6 and the novel antagonist agrelax (1 g/l, 20 l intranasally) also reduced both feeding behavior and intensity of self-stimulation under these conditions. Conclusion. Ghrelin and dopamine receptors are involved in emotional overeating. A novel ghrelin receptor antagonist agrelax reduces emotional overeating induced by 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.
{"title":"A NEW GRELIN RECEPTOR ANTAGONIST AGRELAX REDUCES EMOTIONAL OVEREATING CAUSED BY STIMULATION OF THE LATERAL HYPOTHALAMUS REWARD ZONE IN WELL-FED RATS","authors":"Andrey А. Lebedev, Evgenii Bychkov, Viktoria Lukaskova, Viktor Lebedev, N. Efimov, Petr Shabanov","doi":"10.17816/rcf568925","DOIUrl":"https://doi.org/10.17816/rcf568925","url":null,"abstract":"Relevance. Ghrelin receptor antagonists hold promise for the treatment of eating disorders. The reward zone of the lateral hypothalamus has been proposed as a target mediating the effects of the ghrelin system in emotional overeating. The aim was to study the effects of a new ghrelin receptor antagonist agrelax on emotional overeating induced by stimulation of the reward zone of the lateral hypothalamus in well-fed rats. Materials and methods. Male Wistar rats were trained self-stimulation in a Skinner box. After training, a feeder was placed in the Skinner box and a food conditioned reflex was developed in rats for 5 days. Next, we studied the reaction of food self-deprivation, i.e. behavior under conditions of choice of self-stimulation or food intake. Results. The reaction of food self-deprivation, when the animals did not approach the feeder, was observed at a value more than 10% of threshold current. Self-stimulation of the lateral hypothalamus with 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 intensity of self-stimulation in the food self-deprivation test at thresholds current. The ghrelin receptor antagonists [D-LYS3]-GHRP-6 and the novel antagonist agrelax (1 g/l, 20 l intranasally) also reduced both feeding behavior and intensity of self-stimulation under these conditions. Conclusion. Ghrelin and dopamine receptors are involved in emotional overeating. A novel ghrelin receptor antagonist agrelax reduces emotional overeating induced by 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.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139201780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarng Pureveev, Andrey А. Lebedev, Inessa Karpova, Sergey Tsikunov, Eugenii Bychkov, Petr Shabanov
Relevance. Gambling addiction (gambling) involves frequent repeated episodes of gambling that dominate to the detriment of social, professional, material and family values. Gambling addiction is often combined with posttraumatic stress disorder (PTSD). Objective. To study 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 in rats. 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 1 sunflower seed, each second run in arm 2 was reinforced with 2 seeds, and each third run in arm 3 was reinforced with 3 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, where one of them 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 and Analysis. A decrease in the content of the dopamine metabolite dioxyphenylacetic acid and the ratio of dioxyphenylacetic acid to dopamine content in the prefrontal cortex was shown. A decrease in the content of serotonin, its metabolite 5-hydroxyindoleacetic acid and the ratio of 5-hydroxyindoleacetic acid to serotonin in the prefrontal cortex was also found in rats after exposure to a predator. At the same time, 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 the third arm of the maze, suggesting that the animals exhibited more risky behavior observed in the situation of choosing reinforcements of different strength and probability. Conclusion. The animal model shows that depletion of dopaminergic and serotoninergic systems of the prefrontal cortex underlies pathological gambling addiction and inadequate decision making caused by PTSD.
{"title":"PSYCHIC TRAUMA CAUSES INCREASED IMPULSIVITY IN A MODEL OF GAMBLING ADDICTION BY ALTERING DOPAMINE AND SEROTONIN METABOLISM IN THE PREFRONTAL CORTEX","authors":"Sarng Pureveev, Andrey А. Lebedev, Inessa Karpova, Sergey Tsikunov, Eugenii Bychkov, Petr Shabanov","doi":"10.17816/rcf568121","DOIUrl":"https://doi.org/10.17816/rcf568121","url":null,"abstract":"Relevance. Gambling addiction (gambling) involves frequent repeated episodes of gambling that dominate to the detriment of social, professional, material and family values. Gambling addiction is often combined with posttraumatic stress disorder (PTSD). Objective. To study 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 in rats. 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 1 sunflower seed, each second run in arm 2 was reinforced with 2 seeds, and each third run in arm 3 was reinforced with 3 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, where one of them 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 and Analysis. A decrease in the content of the dopamine metabolite dioxyphenylacetic acid and the ratio of dioxyphenylacetic acid to dopamine content in the prefrontal cortex was shown. A decrease in the content of serotonin, its metabolite 5-hydroxyindoleacetic acid and the ratio of 5-hydroxyindoleacetic acid to serotonin in the prefrontal cortex was also found in rats after exposure to a predator. At the same time, 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 the third arm of the maze, suggesting that the animals exhibited more risky behavior observed in the situation of choosing reinforcements of different strength and probability. Conclusion. The animal model shows that depletion of dopaminergic and serotoninergic systems of the prefrontal cortex underlies pathological gambling addiction and inadequate decision making caused by PTSD.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"1261 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139202869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bakhodir Daliev, Evgenii R. Bychkov, Andrey А. Lebedev, P. Shabanov, Leonid V. Myznikov
The search for new neuroactive compounds that have a selective effect on the mechanisms of emotional reinforcement in gambling addiction is of interest. There have been no previous studies on the effects of coumarins on gambling addiction. Aim. The aim of our work was to study 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 effect of 6 coumarin derivatives was studied - LVM-091, LVM-092, LVM-096, LVM-099, LVM-S144, IEM-2886 Results and its discussion. In the burrowing balls test, substances synthesized on the basis of coumarin LVM-092, LVM-099, LVM-S144, IEM-2886 reduced the level of compulsivity, reducing the number of buried balls compared to the control group and the diazepam group (p0.05). 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. Conclusion. New coumarin derivatives cause an anticompulsive effect and reduce the level of impulsivity in rats, which in the future can be used in the treatment of obsessive-compulsive disorders and addictive conditions, such as Internet addiction and gaming addiction.
{"title":"Neurotropic effect of new coumarin derivatives on the impulsive and compulsive components of gambling addiction in rats.","authors":"Bakhodir Daliev, Evgenii R. Bychkov, Andrey А. Lebedev, P. Shabanov, Leonid V. Myznikov","doi":"10.17816/rcf569408","DOIUrl":"https://doi.org/10.17816/rcf569408","url":null,"abstract":"The search for new neuroactive compounds that have a selective effect on the mechanisms of emotional reinforcement in gambling addiction is of interest. There have been no previous studies on the effects of coumarins on gambling addiction. Aim. The aim of our work was to study 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 effect of 6 coumarin derivatives was studied - LVM-091, LVM-092, LVM-096, LVM-099, LVM-S144, IEM-2886 Results and its discussion. In the burrowing balls test, substances synthesized on the basis of coumarin LVM-092, LVM-099, LVM-S144, IEM-2886 reduced the level of compulsivity, reducing the number of buried balls compared to the control group and the diazepam group (p0.05). 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. Conclusion. New coumarin derivatives cause an anticompulsive effect and reduce the level of impulsivity in rats, which in the future can be used in the treatment of obsessive-compulsive disorders and addictive conditions, such as Internet addiction and gaming addiction.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139198011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander L. Urakov, Natalya A. Urakova, Alexey P. Reshetnikov, Petr D. Shabanov, Yi Wang, Prdeep Bodduluri, A. Samorodov, Poman A. Rozov, Albina A. Shchemeltva, Vasily E. Novikov, E. V. Pozhilova
It is shown that traditional treatment of chronic wounds is a course of daily single procedures of cleansing the wound surface from purulent-necrotic masses by mechanical and medicinal methods, accompanied by regular renewal of wound dressings. In this case, the procedures of medicinal wound cleansing last 10 - 15 minutes between the replacement of "old" wound dressings with "new" wound dressings. According to the established practice, medicinal sanitation of infected and purulent wounds during dressings consists in irrigation of the wound surface with cleansing solutions, solutions of 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 dressings until complete cleansing of wounds from pus. Nevertheless, the effectiveness of the generally accepted course treatment of chronic wounds remains insufficiently high. It is reported that the use of pyolytics and their supplementation with wound dressings made in the form of warm wet compresses, which create a local greenhouse effect in wounds, can accelerate the healing of chronic wounds. It is shown that pyolytics is a group of antiseptics developed in Russia, which are warm alkaline solutions of hydrogen peroxide, which in interaction with purulent-necrotic masses very quickly dissolve and foam them. As a result of interaction with pyolytics, thick purulent immediately turns into fluffy oxygenated foam. It is shown that pyolytics have been developed due to physicochemical repurposing of aqueous solutions of sodium hydrogen carbonate and hydrogen peroxide. To accelerate the healing of chronic wounds it was proposed to irrigate the surface of chronic wounds with a solution of 3% hydrogen peroxide and 2-10% sodium bicarbonate, heated to a temperature of +37 - +45C, having alkaline activity at pH 8.4 - 8.5 and enriched with dissolved carbon dioxide or oxygen (due to excess pressure of 0.2 ATM). The essence of the invented technology of treatment of chronic wounds with the use of pyolytics is indicated and the results of treatment of chronic wounds with pyolytics in combination with warm moist dressings-compresses are given, which confirm the presence of wound-healing effect. Consequently, physical and chemical re-profiling of antiseptics allows turning them into effective pyolytics, and the combination of pyolytics with warm wound dressings made in the form of warm moist compresses, which create a local greenhouse effect in wounds, allows accelerating the healing of chronic wounds.
{"title":"Pyolytics as a products of physical-chemical repurposing of antiseptics and an alternative to larval therapy for chronic wounds","authors":"Alexander L. Urakov, Natalya A. Urakova, Alexey P. Reshetnikov, Petr D. Shabanov, Yi Wang, Prdeep Bodduluri, A. Samorodov, Poman A. Rozov, Albina A. Shchemeltva, Vasily E. Novikov, E. V. Pozhilova","doi":"10.17816/rcf606648","DOIUrl":"https://doi.org/10.17816/rcf606648","url":null,"abstract":"It is shown that traditional treatment of chronic wounds is a course of daily single procedures of cleansing the wound surface from purulent-necrotic masses by mechanical and medicinal methods, accompanied by regular renewal of wound dressings. In this case, the procedures of medicinal wound cleansing last 10 - 15 minutes between the replacement of \"old\" wound dressings with \"new\" wound dressings. According to the established practice, medicinal sanitation of infected and purulent wounds during dressings consists in irrigation of the wound surface with cleansing solutions, solutions of 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 dressings until complete cleansing of wounds from pus. Nevertheless, the effectiveness of the generally accepted course treatment of chronic wounds remains insufficiently high. It is reported that the use of pyolytics and their supplementation with wound dressings made in the form of warm wet compresses, which create a local greenhouse effect in wounds, can accelerate the healing of chronic wounds. It is shown that pyolytics is a group of antiseptics developed in Russia, which are warm alkaline solutions of hydrogen peroxide, which in interaction with purulent-necrotic masses very quickly dissolve and foam them. As a result of interaction with pyolytics, thick purulent immediately turns into fluffy oxygenated foam. It is shown that pyolytics have been developed due to physicochemical repurposing of aqueous solutions of sodium hydrogen carbonate and hydrogen peroxide. To accelerate the healing of chronic wounds it was proposed to irrigate the surface of chronic wounds with a solution of 3% hydrogen peroxide and 2-10% sodium bicarbonate, heated to a temperature of +37 - +45C, having alkaline activity at pH 8.4 - 8.5 and enriched with dissolved carbon dioxide or oxygen (due to excess pressure of 0.2 ATM). The essence of the invented technology of treatment of chronic wounds with the use of pyolytics is indicated and the results of treatment of chronic wounds with pyolytics in combination with warm moist dressings-compresses are given, which confirm the presence of wound-healing effect. Consequently, physical and chemical re-profiling of antiseptics allows turning them into effective pyolytics, and the combination of pyolytics with warm wound dressings made in the form of warm moist compresses, which create a local greenhouse effect in wounds, allows accelerating the healing of chronic wounds.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"195 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139243329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The literature review reflects the contemporary information on the role of oxidative stress in the pathogenesis of autism spectrum disorders. We present data on the importance of genetic predisposition, environmental factors, and epigenetic influences on the development of oxidative stress, which, during critical periods of early brain development, may influence the induction and progression of the disease. The role of mitochondrial dysfunction, immunological disorders, increased permeability of the blood-brain barrier, hypoperfusion of the brain causing or aggravating the redox imbalance in patients with autism spectrum disorders is shown. Analysis of the literature data indicates that the increased content of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione, ceruloplasmin and transferrin in the blood and brain of patients with autism spectrum disorders reflects the activation of compensatory mechanisms. Increased levels of malondialdehyde, xanthine oxidase, nitric oxide in various biological media indicate insufficiency of antioxidant protection system. Taking into account the role of oxidative stress in the pathogenesis of autism spectrum disorders, therapy including antioxidant drugs is indicated for correction of metabolic disorders.
{"title":"Role of oxidative stress in the pathogenesis of autism spectrum disorders","authors":"Svetlana G. Belokoskova, Sergey G. Tsikunov","doi":"10.17816/rcf567781","DOIUrl":"https://doi.org/10.17816/rcf567781","url":null,"abstract":"The literature review reflects the contemporary information on the role of oxidative stress in the pathogenesis of autism spectrum disorders. We present data on the importance of genetic predisposition, environmental factors, and epigenetic influences on the development of oxidative stress, which, during critical periods of early brain development, may influence the induction and progression of the disease. The role of mitochondrial dysfunction, immunological disorders, increased permeability of the blood-brain barrier, hypoperfusion of the brain causing or aggravating the redox imbalance in patients with autism spectrum disorders is shown. Analysis of the literature data indicates that the increased content of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione, ceruloplasmin and transferrin in the blood and brain of patients with autism spectrum disorders reflects the activation of compensatory mechanisms. Increased levels of malondialdehyde, xanthine oxidase, nitric oxide in various biological media indicate insufficiency of antioxidant protection system. Taking into account the role of oxidative stress in the pathogenesis of autism spectrum disorders, therapy including antioxidant drugs is indicated for correction of metabolic disorders.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"63 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136295366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrey А. Lebedev, Sarng S. Pyurveev, Natalia D. Nadbitova, Aleksey V. Lizunov, Eugenii R. Bychkov, Valeriya V. Lukashova, Natalia R. Evdokimova, Maria A. Netesa, Viktor A. Lebedev, Petr D. Shabanov
BACKGROUND: Factors that may trigger episodes of binge eating include mental and physical stress, dietary restrictions of high-calorie foods. In a rodent model it has been shown that intermittent consumption of high-calorie foods causes binge eating regardless of body weight gain.
AIM: To investigate the effect of a novel ghrelin receptor antagonist Agrelax on binge eating in in adult rats after maternal deprivation in early ontogeny.
MATERIALS AND METHODS: Animals were weaned for 180 min from day 2 to day 12 after birth; males 90100 days of age were used in the experiments. In the development of binge eating, animals received a high-carbohydrate diet (Nutella paste based chocolate mixture) for 1 h every day or every third day for 1.5 months. Fifteen minutes before feeding, the chocolate paste was placed within 5 cm of reach with visual contact. Agrelax, a novel ghrelin receptor antagonist, was administered intranasally 1g/1l, 20l for 7 days.
RESULTS: Maternal deprivation induced bindge eating of high-calorie foods in adult rats. When chocolate was given 3 times a week, its consumption increased (p 0.001) in the maternal deprivation group relative to the control group. After a course of administration of agrelax, chocolate consumption did not differ significantly from that in the control group. The daily consumption of standard food did not differ relative to the control group both before and after the course of agrelax administration. When chocolate was given daily, the maternal deprivation rats did not develop food addiction. At the same time agrelax did not induce a change in chocolate consumption relative to the control group.
CONCLUSIONS: The findings suggest new ways to synthesize pharmacological agents of peptide nature based on ghrelin and its antagonists for correction of food addiction caused by psychogenic stresses in ontogenesis.
{"title":"Reduction of compulsive overeating in rats caused by maternal deprivation in early ontogenesis with the use of a new ghrelin receptor antagonist agrelax","authors":"Andrey А. Lebedev, Sarng S. Pyurveev, Natalia D. Nadbitova, Aleksey V. Lizunov, Eugenii R. Bychkov, Valeriya V. Lukashova, Natalia R. Evdokimova, Maria A. Netesa, Viktor A. Lebedev, Petr D. Shabanov","doi":"10.17816/rcf562841","DOIUrl":"https://doi.org/10.17816/rcf562841","url":null,"abstract":"BACKGROUND: Factors that may trigger episodes of binge eating include mental and physical stress, dietary restrictions of high-calorie foods. In a rodent model it has been shown that intermittent consumption of high-calorie foods causes binge eating regardless of body weight gain.
 AIM: To investigate the effect of a novel ghrelin receptor antagonist Agrelax on binge eating in in adult rats after maternal deprivation in early ontogeny.
 MATERIALS AND METHODS: Animals were weaned for 180 min from day 2 to day 12 after birth; males 90100 days of age were used in the experiments. In the development of binge eating, animals received a high-carbohydrate diet (Nutella paste based chocolate mixture) for 1 h every day or every third day for 1.5 months. Fifteen minutes before feeding, the chocolate paste was placed within 5 cm of reach with visual contact. Agrelax, a novel ghrelin receptor antagonist, was administered intranasally 1g/1l, 20l for 7 days.
 RESULTS: Maternal deprivation induced bindge eating of high-calorie foods in adult rats. When chocolate was given 3 times a week, its consumption increased (p 0.001) in the maternal deprivation group relative to the control group. After a course of administration of agrelax, chocolate consumption did not differ significantly from that in the control group. The daily consumption of standard food did not differ relative to the control group both before and after the course of agrelax administration. When chocolate was given daily, the maternal deprivation rats did not develop food addiction. At the same time agrelax did not induce a change in chocolate consumption relative to the control group.
 CONCLUSIONS: The findings suggest new ways to synthesize pharmacological agents of peptide nature based on ghrelin and its antagonists for correction of food addiction caused by psychogenic stresses in ontogenesis.","PeriodicalId":21186,"journal":{"name":"Reviews on Clinical Pharmacology and Drug Therapy","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136295261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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