Model mass spectrometric study of competitive interactions of antimicrobial bisquaternary ammonium drugs and aspirin with membrane phospholipids

The aim of the study is to reveal molecular mechanisms of possible activity modulation of antimicrobial bis-quaternary ammonium compounds (BQAC) and aspirin (ASP) through noncovalent competitive complexation under their combined introduction into the model systems with membrane phospholipids. Methods. Binary and triple systems containing either decamethoxinum or ethonium, or thionium and aspirin, as well as dipalmitoyl-phosphatidylcholine (DPPC) have been investigated by electrospray ionization mass spectrometry. Results. Basing on the analysis of associates recorded in the mass spectra, the types of nonocovalent complexes formed in the systems studied were determined and the supposed role of the complexation in the BQAC and ASP activity modulation was discussed. The formation of associates of BQAC dications with ASP anion is considered as one of the possible ways of deactivation of ionic forms of the medications. The formation of stable complexes of BQAC with DPPC and ASP with DPPC in binary systems as well as the complexes distribution in triple-components systems BQAC:ASP:DPPC point to the existence of competition between drugs of these two types for the binding to DPPC. Conclusions. The results obtained point to the competitive complexation in the model molecular systems containing the BQAC, aspirin and membrane phospholipids. The observed phenomenon testifies to the possibility of modulating the activity of bisquaternary antimicrobial agents and aspirin under their combined usage, due to the competition between the drugs for binding to the target membrane phospholipid molecules and also due to the formation of stable noncovalent complexes between BQAC and ASP

ПЕРСПЕКТИВНІСТЬ ЗАСТОСУВАННЯ НОВІТНІХ ТА “ЗАБУТИХ” МЕТОДІВ ВИКЛАДАННЯ ФАРМАКОЛОГІЇ У ВИЩІЙ ШКОЛІ

The article considers the role and position of some methods of memorizing large amounts of material at the Department of Pharmacology of M. Pyrohov Vinnytsia National Medical University, as an effective supplemental forms to increase the amount of memory the mastering of knowledge, acquisition of skills of the educational process. There were proposed mnemotechnical methods, one of which is acronyms, fit perfectly into the pedagogical process, help to save time of students, complement and diversify the teaching and to meet the conditions of educational environment of higher education.У статті розглянуті роль та місце деяких прийомів запам’ятовування великої кількості матеріалу на кафедрі фармакології Вінницького національного медичного університету ім. М. І. Пирогова як дієвої допоміжної форми для збільшення обсягу пам’яті, засвоєння студентами знань, набуття умінь та навичок навчального процесу. Запропоновані мнемотехнічні методи, одним із яких є акроніми, органічно вписуються в педагогічний процес, сприяють економії часу студентів, доповнюють та урізноманітнюють викладання, а також відповідають умовам педагогічного середовища вищих навчальних закладів

Mass spectrometry study of ascorbyl palmitate as an agent for nanosomes formation

Background. Study of properties and intermolecular interactions of biologically active compounds which can be used for the purposes of transmembrane drugs delivery is a topical task of modern molecular biophysics. Ascorbyl Palmitate (AP) as a fat-soluble form of vitamin C has recently attracted attention as a promising agent for formation of nanosomes for the “fat insoluble” drug molecules transfer through membranes. However, AP is not sufficiently characterized by up-to-date soft ionization mass spectrometric techniques. Objectives. The aim of the present work is to characterize AP and its intermolecular interactions by a number of mass spectrometric techniques: Electrospray Ionization (ESI), Laser Desorption/Ionization (LDI) and Matrix-Assisted Laser Desorption/Ionization (MALDI). The comparison of these techniques applicability to the study of AP intermolecular interactions as a drug delivery assisting agent is scheduled. Methods. ESI mass spectra are obtained with triple quadrupole Micromass Quattro mass spectrometer. LDI and MALDI experiments are performed by Autoflex II mass spectrometer. Results. In the ESI experiments in the positive ion mode abundant peaks of protonated and cationized AP molecules as well as the peaks of AP clusters nAP•H+ and nAP•Na+ (n=2÷4) are revealed in the mass spectra. This result testifies to the formation of stable noncovalent complexes of the AP molecules in the polar media and confirms the AP ability of formation nanosomes for drug delivery. Analysis of LDI and MALDI mass spectra of AP in positive and negative ion modes shows that in the presence of molecular ions of AP, the peaks of AP dimers or larger AP clusters are not recorded. The ESI probing of the model system containing AP and dipalmitoylphosphatidylcholine (DPPC) reveals stable AP•DPPC•H+ complex which models the AP intermolecular interactions with the phospholipid components of biomembranes and/or liposomes under AP functioning as a drug delivery assisting agent. Conclusions. The current study demonstrates the applicability of all tested mass spectrometric techniques for AP identification in solutions and solid phase, while for the purpose of examining of the AP noncovalent complexes formation and study of AP interactions with biomolecules the ESI is defined as the most effective technique

МІЖДИСЦИПЛІНАРНА ІНТЕГРАЦІЯ ЯК ФАКТОР УДОСКОНАЛЕННЯ ВИКЛАДАННЯ ФАРМАКОЛОГІЇ У МЕДИЧНОМУ ВИШІ

The role and place of interdisciplinary integration are considered in this article as a factor of improving teaching at the Department of Pharmacology in M. Pyrohov Vinnytsia National Medical University. Interdisciplinary connections help to supplement the content of knowledge in one discipline from another, combine them and ensure formation of professionally important skills and abilities. The use of interdisciplinary technologies of doctor’s training allows to rise him on a new level of clinical thinking. This makes him able to solve tasks of medical practice comprehensively, basing on extensive data integration of different disciplines.У статті розглянуті роль та місце міждисциплінарної інтеграції як фактора удосконалення викладання  на кафедрі фармакології Вінницького національного медичного університету ім. М. І. Пирогова. Міждисциплінарні зв’язки допомагають доповнити зміст однієї дисципліни знаннями з іншої, об’єднують їх і забезпечують формування професійно важливих вмінь та навичок. Застосування міждисциплінарних технологій підготовки лікаря дозволяє підняти його на якісно новий рівень клінічного мислення, здатного комплексно вирішувати завдання медичної практики на основі широкого інтегрування даних різноманітних дисциплін

Cardioprotective activity and screening of N-substituted of quinazolin-4(3Н)-ones

Cardioprotection is a promising direction of therapy for myocardial infarction and the search for new substances with cardioprotective properties remains an urgent task in pharmacology. N-substituted quinazolin-4(3H)-ones, which are characterized by antihypoxic, antioxidant, angioprotective, anti-inflammatory, and others properties may have the cardioprotective activity. The purpose of the study is to detect the presence and the degree of cardioprotective effect in a number of N-substituted quinazolin-4(3H)-ones in the model of acute experimental myocardial infarction in different modes of administration, to determine a “structure – action” dependence, to identify a leader compound promising for in-depth study of its pharmacological properties. Materials and methods. 300 non-linear rats of both sexes, weighing 180–220 g, were used in this study. Myocardial infarction was modeled by diathermocoagulation of the coronary artery. In the 1st series of experiments, the studied substances and reference drugs amiodarone, mexidol and thiotriazoline were administered in the prophylactic, and in the 2nd series – in the therapeutic regimen. The cardioprotective effect size was estimated on the basis of the mortality rate of animals. Results. The cardioprotective activity of both the test compounds and reference drugs was evidenced by a decrease in the mortality rate of animals with a heart attack in the critical periods of the experiment relative to the control. The PC-66 has been found to be the most effective: the mortality rate was 20 % versus 54 % of the control in the critical period of the experiment, that is, it was 2.7 times less than in the control. The test substances by the degree of cardioprotective effect in the course of therapeutic introduction into the body can be arranged in the following order: PC-66 = amiodarone ≥ mexidol ≥ thiotriazoline> PC-32 = PC-51. Cardioprotection, the signs of which were found in the PC-66 compound, are well combined with the presence of central analgesic and cerebroprotective effects, which suggests the multifactorial effects of this substance. We can state the originality of the resulting substance and its potential properties. Conclusions. N-substituted quinazolin-4(3H)-ones exhibit cardioprotective activity. 4-(4-oxo-4H-quinazolin-3-yl) benzoic acid (compound PC-66) displays cardioprotective properties the most. The obtained data testify to the prospects of the pharmacological properties and safety of the PC-66 compound in-depth study

Study of intermolecular interactions of antiviral agent tilorone with RNA and nucleosides

Background: While antiviral and interferon-inducing agent tilorone is used as a reactant of a number of popular pharmacological preparations, the molecular mechanisms of its biological antiviral activity are under discussions among the specialists. That is why the molecular level model studies of interactions of tilorone with targeting biomolecules and their components are considered to be urgent and useful for understanding the molecular mechanisms of the agent biological activity. Objectives: The current model study is devoted to mechanistic examining of the intermolecular interactions of tilorone with its possible biomolecular targets which are believed to be nucleic acids and such their components as nucleosides containing purine or pyrimidine nitrogen bases. Materials and methods: The objects of the study are model systems composed of tilorone dihydrochloride (Til•2HCl) and its potential targeting biomolecules: single-stranded RNA (ssRNA) obtained from Saccharomyces cerevisiae yeast or nucleosides - adenosine (Ado), thymidine (Thd), or uridine (Urd). Dynamic light scattering (DLS) measurements aimed at observation of drug-biomolecules aggregation is applied to the system (tilorone+ssRNA) (1:10 molar ratio) in RNA-free phosphate buffered saline solution (with 10% fetal bovine serum). Electrospray ionization (ESI) mass spectrometry is used to examine the intermolecular interactions in the binary (tilorone + nucleoside) (Ado, or Thd, or Urd in 1:10 molar ratio) and triple (tilorone + Ado + Urd) (1:10:10 molar ratio) systems dissolved in polar solvent methanol. Results: The obtained DSL data demonstrate that under conditions similar to the physiological ones, introduction of tilorone into the ssRNA solution results in formation of tilorone+ssRNA aggregates which more than 10 times exceed in size the particles observed in the ssRNA solution itself. The ESI mass spectrometry experiments reveal that while the mass spectra of all studied (tilorone + nucleoside) model systems contain ions characteristic of the individual components of the mixtures, in the spectra of (tilorone + Urd) system the ions of stable ion-molecular clusters of uridine with tilorone dication Urd•Til•2H2+ are recorded. The examining of the three-component model system (tilorone + Ado + Urd) testifies to the selectivity of tilorone binding: while the peak of noncovalent complex of Urd•Til•2H2+ is detected, any peaks of the complexes of Ado with tilorone are not found in the mass spectrum. Conclusions: Formation of large-scale molecular aggregates of tilorone with ssRNA in the solutions which are similar to the physiological solution in physical and chemical characteristics is revealed in the performed DLS investigation. Creation of stable Urd•Til•2H2+ noncovalent complexes in (tilorone + nucleoside) model systems was demonstrated by ESI mass spectrometry, while the complexes of tilorone with Ado and Thd are not detected in the experiments. It testifies to the possibility of formation of stable noncovalent complexes of tilorone with ssRNA and their components in biological systems, and pointed at Urd as one of the potential centers of specific binding of RNA molecules with tilorone

Intermolecular interactions of decamethoxinum and acetylsalicylic acid in systems of various complexity levels

Intermolecular interactions between decamethoxinum (DEC) and acetylsalicylic acid (ASА) have been studied in the phospholipid-containing systems of escalating complexity levels. The host media for these substances were solvents, L-α-dipalmitoylphosphatidylcholine (DPPC) membranes, and samples of human erythrocytes. Peculiar effects caused by DEC-ASА interaction have been observed in each system using appropriate techniques: (a) DEC-ASА non-covalent complexes formation in DPPC-containing systems were revealed by mass spectrometry with electrospray ionization; (b) joint DEC-ASА action on DPPC model membranes led to increasing of membrane melting temperature Tm, whereas individual drugs caused pronounced Tm decreasing, which was demonstrated by differential scanning calorimetry; (c) deceleration of DEC-induced haemolysis of erythrocytes under joint DEC-ASА application was observed by optical microscopy

Опора на тіло як фундамент стійкості самоідентичності особистості

The role of corporality in the formation of the firmness of a person’s self-identity is examined in the article. Our goal was to find out how a person should treat his body so that in the process of social activity, it serves as a support for his self-identity. Mostly we focused on the study of the constructive self-identity of the individual. It is a person’s ability to maintain his integrity and stay true to himself in all life situations. It is clarified that the concept of  «human corporeality» includes interaction not only with one’s own body, but also with other bodies. It is revealed that the study of one’s own corporeality is actualized when a person breaks away from the «body of the family» and must join the «body of the social». Actually, this process can cause a crisis of self-identity. What, in particular, is prompted by the unstable state of our society. Thus, bodily identification has to do with the socialization of the individual. In order to acquire it, the person must master his own body, get used to his own social body and create his own inner culture of caring for the body. The control of one’s own body is an experience of its corporeality, a sense of the significance of its body, the establishment of its limits. Use in the proper social body involves improving it, creating a certain bodily image, which should correspond to the position of a person in society. The internal culture of body care should include a culture of nutrition, a sleep mode, physical activity control, cleanliness and cleanliness of the appearance, etc. It is established that the support of a person to his own body can help him not to lose his identity both in the process of socialization and in social space in general. For this, it is necessary to create a dialogical relationship with your body, the ability to listen to its signals. It is under such conditions that the human body will act to the Other, on which the individual has more chances to preserve his own identity. It is established that in the process of socialization it will be fruitful to first establish relations with the body of the city, as a unit of social space. At the same time, the body of a small town is more organic and natural, so it has better conditions for the individual to existentially open another and to maintain its identity. It is proved that the bodily self must complement the psychic self. Their unity will ensure the person’s constructive steadfastness of self-identity. The latter is symbolically successfully transferred to the plant «water lily».Статья посвящена исследованию роли телесности в формировании стойкости самоидентичности личности. Выяснено, что понятие «телесность человека» включает в себя взаимодействие не только с собственным телом, но и с другими телами. Выявлено, что исследование собственной телесности актуализируется, когда человек отрывается от «тела семьи» и должен присоединиться к «телу социального». Собственно, этот процесс и может вызвать кризис самоидентичности. К чему, в частности, побуждает и нестабильное состояние нашего общества. Таким образом, телесная идентификация имеет отношение к социализации личности. Чтобы ее получить, личность должна овладеть собственным телом, вжиться в собственное социальное тело и создать собственную внутреннюю культуру заботы о теле. Овладение собственным телом является переживанием своей телесности, ощущением значимости своего тела, установлением его границ. Употребление в собственное социальное тело предполагает совершенствование его создания определенного телесного имиджа, который должен соответствовать положению человека в обществе. Внутренняя культура заботы о теле должна включать культуру питания, режим сна, контроль физических нагрузок, чистоту и опрятность внешнего вида и т. п. Установлено, что опора человека на собственное тело может помочь ему не потерять собственную идентичность как в процессе социализации, так и в социальном пространстве вообще. Для этого необходимо создание диалогических отношений со своим телом, умение прислушиваться к его сигналам. Именно при таких условиях тело человека выступит тем Другим, опираясь на которое личность имеет больше шансов сохранить собственную идентичность. Установлено, что в процессе социализации будет плодотворным сначала наладить отношения с телом города как единицей социального пространства. При этом тело маленького городка более органическое и естественное, поэтому в нем лучшие условия для личности, чтобы экзистенциально открыться Другим и сохранить свою самоидентичность. Доказано, что телесная самость должна дополнять психическую самость. Их единство обеспечит личности конструктивную стойкость самоидентичности. Последнюю символически удачно передает растение «водяная лилия».Стаття присвячена дослідженню ролі тілесності у формуванні стійкості самоідентичності особистості. З’ясовано, що поняття «тілесність людини» включає в себе взаємодію не лише з власним тілом, а й з іншими тілами. Виявлено, що дослідження власної тілесності актуалізується, коли людина відривається від «тіла сім’ї» та має долучитися до «тіла соціального». Власне, цей процес і може викликати кризу самоідентичності. До чого, зокрема, спонукає і нестабільний стан нашого суспільства. Тож тілесна ідентифікація має відношення до соціалізації особистості.  Щоб її набути, особистість має опанувати власним тілом, вжитися у власне соціальне тіло та створити власну внутрішню культуру турботи про тіло. Опанування власним тілом є переживанням своєї тілесності, відчуттям значимості свого тіла, встановленням його меж. Вживання у власне соціальне  тіло передбачає вдосконалення його, створення певного тілесного іміджу, який має відповідати становищу людини в суспільстві. Внутрішня культура турботи про тіло має включати культуру харчування, режим сну, контроль фізичних навантажень, чистоту та охайність зовнішнього вигляду і т. п. Встановлено, що опора людини на власне тіло може допомогти їй не втратити власну ідентичність як в процесі соціалізації, так і в соціальному просторі взагалі. Для цього необхідне створення діалогічних стосунків зі своїм тілом, вміння прислухатися до його сигналів.  Саме за таких умов тіло людини виступить тим Іншим, спираючись на яке, людина має більше шансів зберегти власну ідентичність.  З’ясовано, що в процесі соціалізації буде плідним спочатку налагодити стосунки з тілом міста як одиницею соціального простору. При цьому тіло маленького містечка більш органічне і природне, тож в ньому кращі умови для особистості, щоб екзистенціально відкритися Іншим і зберегти свою самоідентичність.  Доведено, що тілесна самість має доповнювати психічну самість. Їх єдність забезпечить особистості конструктивну стійкість самоідентичності. Останню символічно вдало передає рослина «водяна лілія»

Mass spectrometric study of rhamnolipid biosurfactants and their interactions with cell membrane phospholipids

Aim. To examine the formation of supramolecular complexes of biogenous rhamnolipids with membrane phospholipids that is considered as a molecular mechanism of the biosurfactants antimicrobial action. Method. In the present work rhamnolipid biosurfactant samples produced by Pseudomonas sp. PS-17 strain have been investigated by electrospray ionization mass spectrometry for the first time. Results. As a result of the study, characteristic mass spectra of the rhamnolipid samples were obtained, that can be used as reference spectra for mass spectrometric identification of the compounds in any biological or industrial samples. At the next stage of the experiments the pair systems, containing the biosurfactants and a membrane phospholipid dipalmitoylphosphatidylcholine, have been tested. The cationized noncovalent complexes of the rhamnolipids with the phospholipid were observed in the spectra. Conclusions. The results obtained testify to the consideration that rhamnolipids (similar to other membranotropic agents) can form stable supramolecular complexes with membrane phospholipids that are able to evoke the biosurfactants antimicrobial action. A great potential of electrospray ionization mass spectrometry for the biosurfactants identification and study has been demonstrated in the work