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Vol 23, No 8 (2020)


Neuropeptides in the regulation of brain activity in normal and neurodegeneration

Teplyashina E.A., Olovyannikova R.Y., Kharitonova E.V., Lopatina O.L., Kutyakov V.A., Pashchenko S.I., Pozhilenkova E.A., Salmina A.B.


An analysis of the literature containing information on the participation of neuropeptides in the development of brain diseases was carried out. Changes in the production, processing and secretion of neuropeptides, the activity of signaling mechanisms with their participation are responsible for the formation of different variants of neurological deficits (cognitive, behavioral, etc.). As a rule, neuropeptides or otherwise biologically active molecules in the body can function as neurotransmitters, neuromodulators, or neurohormones that perform cognitive and behavioral functions. These biologically active molecules are localized in cells in secretory vesicles, which are delivered from the body of nerve cells to nerve endings and act through Gp-conjugated receptors. The action of neuropeptides has been significantly studied relative to pathological conditions of the brain. So, the mechanism of development of Alzheimer's disease is associated with a diverse spectrum of neuropeptides such as ghrelin, neurotensin, pituitary activating adenylates cyclase polypeptide, neuropeptide Y, neuropeptide P, orexin. This disease is characterized by the accumulation of amyloid β (represented by two forms - Api-42, Api-40) in the brain tissue, which is due to an imbalance in the activity of secretases. The target of action is the precursor protein (APP). The form of the Aβ1-42 peptide has a destructive effect on the cell, this is due to a multidirectional effect: damage to mitochondria, an increase in the sensitivity of neurons to the effects of glutamate, impaired calcium metabolism, and a slowdown in metabolic transformations of glucose. Aβ peptide is characterized by the performance of a key function in synaptic transmission of a nerve impulse and enhanced synaptic transmission between two neurons for a long time. The pathological picture of Alzheimer's disease is characterized by significant expression of apolipoprotein E (APOE) in the brain tissue, which forms local cell clusters of amyloid β with Aβ, a decrease in the number of neurons expressing proopiomelanocortin (POMC), neuropeptide Y (NPY) and agouti-like peptide (AgRP) genes that change brain activity. As a result, expression of genes responsible for the synthesis of proteins of the immune system, early development of neuroinflammation and activation of apoptosis is also noted. Thus, neuropeptides are considered not only as biomarkers of pathological conditions, but also as targets for pharmacological preparations.
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):3-10
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Effect of the parameters regulation of the nanoparticulate form of doxorubicin based on PLGA on the distribution between human blood plasma and red blood cells

Kovshova T.S., Osipova N.S., Belov A.V., Maksimenko O.O., Balabanyan V.Y., Gelperina S.E.


Relevance. One of the features of the pharmacokinetics of nanoparticle-based drug formulations is the different distribution of free and carrier-bound drugs (nanoparticles, liposomes) between plasma and blood cells. Aim. Evaluation of in vitro binding of doxorubicin-loaded nanoparticles (NPs) based on a copolymer of lactic and glycolic acids (PLGA) modified with poloxamer 188 (Dox-PLGA) to human red blood cells at a concentration of 10-100 μg/ml and the influence of physicochemical parameters of NPs on their binding to red blood cells. Material and methods. Dox-PLGA NPs were obtained by a "double emulsion" method. A 1% PVA solutions in phosphate buffer at pH 7.4 (Dox-PLGA/7.4) and 6.4 (Dox-PLGA/6.4) were used as the external aqueous phase. The purified Dox-PLGA/7.4(G-25) and Dox-PLGA/6.4(G-25) NPs were obtained by separation of the free fraction of doxorubicin (non-nanoparticle-bound) by gel filtration. The kinetics of doxorubicin release from NPs in vitro was determined in a 1% solution of poloxamer 188. To assess the binding of the NPs to red blood cells, the distribution coefficients KRBC/Plasma (red blood cells - plasma) and KBlood/Plasma (whole blood - plasma) were calculated after incubation in whole blood within 5, 15 and 30 minutes. The doxorubicin content in plasma was estimated by HPLC. Results. Compared to the Dox-PLGA/7.4 NPs (average size 114±1 nm), the Dox-PLGA/6.4 NPs (average size 142±2 nm) had a lower encapsulation efficiency (79.7±1.1% vs 91.0±0.7%, respectively) and a higher release rate of doxorubicin in vitro. Based on the calculated KBlood/Plasma values, the total amount of doxorubicin bound to red blood cells after 5 minutes of incubation was ~ 33% for both nanoparticulate formulations and free doxorubicin (control) over the entire concentration range. The equilibrium degree of binding (after 15 minutes of incubation) was 58-63% for free doxorubicin, 57-58% for Dox-PLGA/6.4 and 46-49% P LG A/7.4. The Dox-PLGA/6.4(G-25) NPs had the lowest equilibrium degree of binding to red blood cells (~ 34%). Conclusion. Binding of the nanoparticle-bound doxorubicin (Dox-PLGA) to human red blood cells evaluated in vitro in the concentration range of 10-100 μg/ml is lower as compared with free doxorubicin. The NPs with a higher encapsulation efficiency and loading of doxorubicin exhibit lower distribution coefficients of doxorubicin between red blood cells and blood plasma (KBlood/Plasma and KRBC/Plasma)
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):11-18
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Development of the composition and technology of capsules containing Vitis vinifera L. leaf red extract dry

Kachalina T.V., Malysheva N.A., Semkina O.A., Djavakhyan M.A.


Relevance. Development of dosage forms for the treatment of chronic venous insufficiency is an actual task of pharmaceutical technology due to the high prevalence of this disease. The extract has antioxidant, capillary-strengthening, anti-sclerotic, cardiovascular and anti-inflammatory effects. The aim of the study was to develop the composition and technology of hard gelatin capsules containing Vitis vinifera L. red leaves dry extract to expand the range of domestic drugs with a venotonic effect. Objects of research: Vitis vinifera L. red leaves dry extract. Excipients: corn starch CleanSet 03703 (Cargill, the Netherlands), dex-tran Emdex (Dextrates-JRS Pharma), lactose 80M (Lactochem Crystals, the Netherlands), microcrystalline cellulose MCC-101 (JRS Pharma, Germany), calcium stearate (Himmed, Russia), Aerosil A380 (GOST 14922-77). Results. The composition and production technology of capsules containing Vitis vinifera L. red leaves dry extract are substantiated. The quality indicators of Vitis vinifera L. red leaves dry extract in dosage form - capsules - were determined: appearance, uniformity of capsule mass, disintegration of capsules, authenticity, quantitative content of the sum of phenolic compounds in terms of rutin. All quality indicators comply with the requirements of the draft regulatory documentation "Vitis vinifera L. red leaves dry extract, 180 mg capsule". Conclusion. Based on the results obtained, the composition of the capsules was developed: Vitis vinifera L. red leaves dry extract, corn starch, aerosil, calcium stearate. The developed composition made it possible to obtain a mass for encapsulation by simply mixing the ingredients, followed by filling hard gelatin capsules. Capsules with Vitis vinifera L. red leaves dry extract expand the range of medicines for the prevention and treatment of chronic venous insufficiency.
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):19-25
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Development and validation of HPLC-MS/MS method of determination of a new derivative of valproleic acid and 1,3,4-thiadiazole in rabbit blood plasmafor pharmacokinetic study

Malygin A.S., Popov N.S., Demidova M.A., Shatokhina N.A.


Objective. To develop and validate the HPLC-mass spectrometric method for determining a new derivative of valproic acid and 1,3,4-thiadiazole in rabbit plasma. Material and methods. The object of the study was N-(5-ethyl-1,3,4-thiadiazol-2-yl) -2-propylpentanamide (valprazolamide) - a new antiepileptic drug from the group of thiadiazole derivatives of valproic acid. Valprazolamide was determined in rabbit plasma using an Agilent 1260 Infinity II high performance liquid chromatograph (Agilent Technologies, Germany). An AB Sciex QTrap 3200 MD triple quadrupole mass spectrometer (AB Sciex, Singapore) with an electrospray ion source (Turbo V with a TurboIonSpray probe) was used as a detector. Selectivity, carry over, linearity, accuracy, precision, matrix effectand recovery were evaluated for the developed method. Results. A method of HPLC-mass spectrometric determination of valprazolamide in rabbit plasma was developed (Phenomenex Synergi C18 analytical column 4 μm 2.0 x 50 mm, gradient elution: 0-1 minute 10% aqueous acetonitrile solution; 1-3 minutes linear increase in concentration acetonitrile in a mixture up to 90%; 3-4 minutes isocratic section with an acetonitrile concentration of 90%; 4-5 minutes conditioning the column with a 10% solution; flow rate of the mobile phase - 0.6 ml / min; volume of sample injected -20 μl; total time gradient elution - 5 min t; mass spectrometric detection). Mass detection conditions: positive polarization, voltage of the electrospray 5500.0 V, declustering potential 41.0; the curtain gas pressure is 20.0 psi, the spray gas is 40.0 psi, the input potential is 3.5 V. The MRM transitions for valprazolamide were m/z 256.1 → m/z 130.1 and m/z 81.0. Acetazolamide (m/z 223.1 → m/z 73.0) was used as an internal standard. Conclusion. The analytical range of the method for determining valprazolamide is 1-1000 ng/ml. The developed method is selective, accurate, precision and linear, it meets the requirements for the validation of bioanalytical methodsin all respects.
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):26-33
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Programmed use of extracorporeal photochemotherapy in the complex treatment of Devergey’s disease

Manuilov A.S., Belsky A.N., Bardakov S.N., Apchel A.V.


Relevance. One of the promising areas of modern medicine is the method of efferent therapy, selectively affecting the mechanisms of the immune system and homeostasis. The lack of effectiveness of drugs, their side effects and the emerging pharmacoresistance in patients with Devergy disease, contribute to the search for new methods of treatment based on extracorporeal photochemical treatment of peripheral blood cells. Objective. To study the clinical and pathogenetic significance of the programmed use of extracorporeal photochemotherapy in the complex treatment of Devergey's disease. Material and methods. Using the method of extracorporeal photochemotherapy, a programmed treatment of a patient with Devergy disease was carried out for 12 months. Results. In an in vitro study with incubation of cell media, it was found that the extracorporeal photochemotherapy technique induces lymphocyte apoptosis with maximum levels on the third day after the procedure, which confirms the pathogenetic significance of this technique in the complex treatment of patients with Devergee's disease. Conclusions. The inclusion of programmed extracorporeal photochemotherapy in the complex therapy of a patient with Devergey's disease made it possible to stop a very high activity of the disease, reduce the dosage of acetritin preparations and achieve long-term remission (more than 12 months of observation).
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):34-39
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Some aspects of pre-clinical study of safety of the Lycopus europaeus L. dry extract

Krepkova L.V., Babenko A.N., Lemyaseva S.V., Borovkova M.V., Kuzina O.S.


Relevance. Currently used medicine drugs are quite effective, but with prolonged use can cause serious side effects. Recently, there has been considerable interest in the use of herbal drugs that can influence the functional activity and structure of the thyroid gland. One of the promising objects, based on which scientific research is conducted, is the Lycopus europaeus L. (Lamiaceae), which has a thyroostatic effect. The purpose. To evaluate the general toxic effect of the dry extract of Lycopus europaeus L. during prolonged introduction to rats to determine the prospects of creating a new thyrotropic drug on its basis. Material and methods. A chronic experiment has conducted on male and female Wistar rats in accordance with the "Guidelines for conducting preclinical studies of drugs". Dry extract of Lycopus europaeus L. in the form of freshly prepared 1%, 5% and 10% aqueous suspensions haveintroducted into stomach for 90 days at doses of 50, 250 and 750 mg / kg. The integral health indicators of experimental animals have recorded, peripheral blood samples have taken to determine hematological and biochemical parameters, the functional state of the cardiovascular system (ECG study) has studied, the excretory function of the kidneys has compared with 3% of the water load; study of the central nervous system - according to indicative reactions in the test "open field". At the end of the experiment, histological studies of the internal organs of experimental animals have performed. Results. Introduction the dry extract of Lycopus europaeus L. to the stomach of clinically healthy rats of both sexes fora long time at doses of 50, 250, 750 mg / kg. had a sedative effect, as well as a dose-dependent hypothyroid effect has shown. Prolonged introduction of the studied extract in 40- and 125-fold therapeutic doses (250 and 750 mg / kg) caused a moderate toxic effect on the liver and tubular apparatus of the kidneys. The threshold dose is set to 50 mg / kg. Conclusion. The results of the studies made a new thyroid-stimulating drug of systemic action (0.200 g capsules), based on the extract studied, and recommend it for conducting clinical studies, observing the therapeutic dose and caution for use in patients with liver and kidney diseases.
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):40-47
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The level of stearoyl-CoA-desaturase in the lenses of rat eyes in cataract progression

Chuprov A.D., Treushnikov V.M., Notova S.V., Kim S.M., Marshinskaia O.V., Kazakova T.V.


Relevance. Studies are underway intensively around the world to identify the causes and mechanisms of cataract development. The special attention is paid to the study of stearoyl-CoA-desaturase enzymes. There are data indicating the involvement of the level changes of desaturases in ophthalmic pathologies in the literature. Work objective. To establish the presence of stearoyl-CoA-desaturase in the lenses of the eyes and study the change of level of this enzyme in cataract progression on the experimental model. Material and methods. The study was conducted on Wistar rats (n=60). Two groups were formed: control (n=30) and experimental (n=30). The animals of the experimental group were simulated age-related cataract using ultraviolet radiation for 6 months. The lenses were taken to determine the content of stearoyl-CoA-desaturase every two months. The study used an enzyme immunoassay. Results. The level of stearoyl-CoA-desaturase in cataract lenses was lower by 53% (p=0.027), 55.8% (p=0.008) and 53.3% (p=0.018) at 2, 4, and 6 months of disease development respectively relatively healthy animals. Conclusions. The study confirmed the presence of stearoyl-CoA-desaturase in the tissues of the lens of the eye. Cataract progression is associated with the level decrease of this enzyme. The results of the study demonstrate the adaptive changes occurring in the lenses of the eyes against the background of cataract development. In this experiment using healthy animals, the level decrease of desaturase in the lens is not a pathogenic factor.
Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):48-51
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Professor Vladimir Viktorovich Rozanov (k 70-letiyu so dnya rozhdeniya)

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Problems of Biological Medical and Pharmaceutical Chemistry. 2020;23(8):52-54
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