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Effect of sphingosine phosphorylcholine on the stratum corneum permeability
Bataalla, Khalied Mahrous Farid ; Kováčik, Andrej (advisor) ; Vraníková, Barbora (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of pharmaceutical technology Candidate: Khalied Mahrous Farid Bataalla Supervisor: PharmDr. Andrej Kováčik, Ph.D. Adviser: Dr. Georgios Paraskevopoulos, PhD. Title of Diploma Thesis: Effect of Sphingosine Phosphorylcholine on the stratum corneum Permeability Sphingosine phosphorylcholine (SPC) is a sphingolipid, which belongs to a lysolipid family. This compound, formed from ceramide precursor - sphingomyelin by the action of sphingomyelin deacylase, is composed of sphingoid base (e.g., sphingosine) and phosphorylcholine moiety joined to a hydroxyl group. In this project, we studied how SPC influences the barrier function and microstructure of model stratum corneum (SC) membranes. Four permeability markers were used to study the permeability of SPC: electric impedance, trans-epidermal water loss (TEWL), flux of indomethacin and flux of theophylline. From this study we found out that the addition of SPC significantly increases the permeability to water and ions (increased values of TEWL and decreased values of electric impedance). This trend was also observed on third (permeability to theophylline) and fourth (permeability to indomethacin) permeation markers. The detrimental effect of SPC was also studied in biophysical experiments...
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Study of microstructure of skin barrier model using deuterated ceramides
Juhaščik, Martin ; Kováčik, Andrej (advisor) ; Paraskevopoulos, Georgios (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Author: Martin Juhaščik Supervisor: PharmDr. Andrej Kováčik, Ph.D. Title of diploma thesis: Study of microstructure of skin barrier model using deuterated ceramides Ceramides (Cer) are sphingolipids, which participate in eucaryotic cells in various biological processes (cell signalling, proliferation, differentiation and cell apoptosis). In mammalian skin, Cer are localized in the uppermost layer of epidermis, stratum corneum (SC). In this layer, Cer along with cholesterol (Chol) and free fatty acids form multilayer lamellae of intercellular lipid matrix. The skin lipid arrangement in SC is still unclear. To evaluate the skin lipid arrangement, skin membrane models with labelled (deuterated) lipids have been used. Therefore, the aim of this work was to synthesize sphingosine with deuterated chain and Cer based on deuterated sphingosine, i.e., N-lignoceroyl sphingosine-d28 (with lignoceric acid acyl (C24); d-CerNS) and N-lignoceroyl-d47 sphingosine-d28 (dd-CerNS) and to study their phase behaviour and arrangement in model membranes by using biophysical studies. Synthesis of deuterated Cer started from elimination of 1-pentadecanol-d31 to obtain a deuterated terminal alkene. Next, a vinylation of...
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Effect of compaction pressure on the compressibility of liquisolid powders containing Neusilin US2
Čurmová, Dominika ; Vraníková, Barbora (advisor) ; Kováčik, Andrej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Student: Dominika Čurmová Supervisor: PharmDr. Barbora Vraníková, Ph.D. Title of Diploma Thesis: Effect of compaction pressure on the compressibility of liquisolid powders containing Neusilin® US2 Preparation of the liquisolid systems seems to be very promising method for increasing bioavailability of poorly water-soluble drugs. The aim of this thesis was to evaluate the effect of the compression force on the viscoelastic properties of liquisolid mixtures containing Neusilin® US2 (carrier) and macrogol 400 (solvent). The force - displacement record was employed as an evaluation method. Furthermore, the influence of the compression pressure on the parameters of the compressed tablets was determined using pharmacopoeial tests (mass uniformity, hardness, friability and disintegration time of the tablets). Moreover, the height, diameter and pycnometric density of all samples was measured. From the obtained results it can be stated that the energy values were increasing with increasing compression force, while plasticity was decreasing. The hardness of liquisolid tablets was also increasing with increasing compression force, while the friability of the tablets decreased. The results showed that in the case...
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Novel amino-decorated polyamidoamine dendrimers with ethylenediamine core: Synthesis and potential application in (trans)dermal drug delivery
Langerová, Martina ; Paraskevopoulos, Georgios (advisor) ; Kováčik, Andrej (referee)
Dendrimers are characterized as synthetic, spherical macromolecules with tree- like branched structures. Their well-controlled sizes (3 - 10 nm), ease of functionalization, high water solubility, well-defined chemical structure, and biocompatibility make these nanomaterials attractive for a wide spectrum of promising biomedical applications. Peptide dendrimers and polyamidoamine (PAMAM) dendrimers have been used to date as effective transdermal or topical drug delivery systems, with the latest in a much greater extent. The structural characteristics of the aforementioned molecules guided us to design a novel repeating unit for dendrimers (monomer) possessing amino branching point and able to afford generation expanding through repeating amide bonds. The novel monomer, after appropriate modifications, was used to develop lower generations of polyamidoamino dendritic structures having amide groups and amino-branching points in their interior. The new dendrimers were isolated and fully characterized by typical spectroscopic technics. The final molecules will be used in human skin permeation experiments and will be evaluated for their effect on skin permeability.
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Synthesis of novel huprine derivatives as potential cholinesterase inhibitors
Pokrievková, Lucia ; Roh, Jaroslav (advisor) ; Kováčik, Andrej (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Organic And Bioorganic Chemistry Student: Lucia Pokrievková Supervisor: doc. PharmDr. Jaroslav Roh, Ph.D. Supervisor specialist: RNDr. Eva Mezeiová, Ph.D., PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis of novel huprine derivatives as potential cholinesterase inhibitors Alzheimer's disease (AD) is a complex neurodegenerative disease that is manifested by the gradual loss of short-term and, at more advanced stages, also of long-term memory. The characteristic histopathological features of AD is the presence of neuritic plaques and neurofibrillary tangles in affected brain regions. Cholinergic neurotransmission is also one of the key pathological findings in AD. Only two drug groups are used in AD therapy. The first group consists of acetylcholinesterase inhibitors (AChEIs). Memantine, which is a glutamate receptors antagonist, belongs to the second one. The aim of the diploma thesis was the synthesis of a new group of drugs acting as multipotent ligands (multi-target directed ligands, MTDLs) derived from huprines. The new compounds were designed to be able to interact with both anionic sites of acetylcholinesterase (AChE), thereby exaggerating the enzyme-inhibiting effect. In the experimental part of the diploma...
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Study of substituted arylguanidines as potential drugs XIV.
Kobosilová, Jana ; Palát, Karel (advisor) ; Kováčik, Andrej (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Organic and Bioorganic Chemistry Author: Jana Kobosilová Supervisor: PharmDr. Karel Palát, CSc. Title of bachelor thesis: Study of substitued arylguanidines as potencial drugs XIV. In view of the increasing number of fungal pathogens and the increased resistance of these pathogens to already available antifungal agents, a new structure inhibiting the growth of these pathogens must be sought. In the area of guanidine-derived substances, a worldwide research is taking place, which is also attended by the Faculty of Pharmacy in Hradec Králové. As part of my bachelor thesis, five previously unpublished substances have been synthesized: hexadecyl(4-methyl-2-nitrophenyl) sulfide 2-(hexadecylsulfanyl)-5-methylaniline 2-(hexadecylsulfanyl)-5-methylanilinium chloride 2-[2-(hexadecylsulfanyl)-5-methylphenyl]guanidinium nitrate 2-[2-(hexadecylsulfanyl)-5-methylphenyl]-1,1-dimethylguanidine
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Novel amino-decorated polyamidoamine dendrimers with ethylenediamine core: Synthesis and potential application in (trans)dermal drug delivery
Langerová, Martina ; Paraskevopoulos, Georgios (advisor) ; Kováčik, Andrej (referee)
Dendrimers are characterized as synthetic, spherical macromolecules with tree- like branched structures. Their well-controlled sizes (3 - 10 nm), ease of functionalization, high water solubility, well-defined chemical structure, and biocompatibility make these nanomaterials attractive for a wide spectrum of promising biomedical applications. Peptide dendrimers and polyamidoamine (PAMAM) dendrimers have been used to date as effective transdermal or topical drug delivery systems, with the latest in a much greater extent. The structural characteristics of the aforementioned molecules guided us to design a novel repeating unit for dendrimers (monomer) possessing amino branching point and able to afford generation expanding through repeating amide bonds. The novel monomer, after appropriate modifications, was used to develop lower generations of polyamidoamino dendritic structures having amide groups and amino-branching points in their interior. The new dendrimers were isolated and fully characterized by typical spectroscopic technics. The final molecules will be used in human skin permeation experiments and will be evaluated for their effect on skin permeability.
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Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes
Kováčik, Andrej ; Vávrová, Kateřina (advisor) ; Uhriková, Daniela (referee) ; Šklubalová, Zdeňka (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Organic and Bioorganic Chemistry Candidate Mgr. Andrej Kováčik Supervisor prof. PharmDr. Kateřina Vávrová, Ph.D. Title of Doctoral Thesis Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes Ceramides (Cer) occur in intracellular spaces of the stratum corneum, the outermost mammalian epidermal layer, where they along with other lipids (free fatty acids, cholesterol) form a skin lipid barrier. Besides sphingosine- (Cer NS) and dihydrosphingosine-based Cer (Cer NdS), in the healthy mammalian epidermis some polar Cer are present, i.e., Cer based on phytosphingosine (with hydroxyl group in position 4, i.e., phytoceramides) and Cer based on 6-hydroxysphingosine (with hydroxyl group in position 6, i.e., 6- hydroxyceramides). However, the role of phytoceramides (Cer NP) and 6 hydroxyceramides (Cer NH) in the skin barrier function has not been clarified. Moreover, 6 hydroxyceramides are not commercially available. Therefore, the first aim of this work was to synthesize physiological 6-hydroxyceramides. The synthesis of 6- hydroxylated Cer, i.e., Cer NH with long (C24:0) and Cer EOH with ultralong acyl with ester-linked linoleic acid is reported. The triple bond was reduced...
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Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes
Kováčik, Andrej ; Vávrová, Kateřina (advisor) ; Uhriková, Daniela (referee) ; Šklubalová, Zdeňka (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Department of Organic and Bioorganic Chemistry Candidate Mgr. Andrej Kováčik Supervisor prof. PharmDr. Kateřina Vávrová, Ph.D. Title of Doctoral Thesis Study of Effect of Ceramide Hydroxylation on Permeability and Microstructure of Model Lipid Membranes Ceramides (Cer) occur in intracellular spaces of the stratum corneum, the outermost mammalian epidermal layer, where they along with other lipids (free fatty acids, cholesterol) form a skin lipid barrier. Besides sphingosine- (Cer NS) and dihydrosphingosine-based Cer (Cer NdS), in the healthy mammalian epidermis some polar Cer are present, i.e., Cer based on phytosphingosine (with hydroxyl group in position 4, i.e., phytoceramides) and Cer based on 6-hydroxysphingosine (with hydroxyl group in position 6, i.e., 6- hydroxyceramides). However, the role of phytoceramides (Cer NP) and 6 hydroxyceramides (Cer NH) in the skin barrier function has not been clarified. Moreover, 6 hydroxyceramides are not commercially available. Therefore, the first aim of this work was to synthesize physiological 6-hydroxyceramides. The synthesis of 6- hydroxylated Cer, i.e., Cer NH with long (C24:0) and Cer EOH with ultralong acyl with ester-linked linoleic acid is reported. The triple bond was reduced...
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Synthesis and study of 6-hydroxysphingosine-based ceramides
Kováčik, Andrej ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Ceramides, belonging to large family of sphingolipids, play a significant role in many processes in living systems. They participate in both physiological and pathophysiological processes (cell signalization). In addition, they are essential in the human epidermis (stratum corneum), where they act as a barrier - they participate in the maintenance of stable internal environment (preventing the penetration of unwanted substances, pathogens and the loss of body water). Ceramide molecules constist of two basic components. Each molecule contains one of the four sphingo-like bases, and a fatty acid acyl, which is either non-substituted or substituted at the position α- or ω-. All these possible combinations give different types of ceramides that occur in the skin. This work focuses on ceramides based on 6-hydroxysfingosin - sphingosine base with a hydroxyl group in the 6-position. Ceramides (acylated bases) of this type were found only in the human epidermis, they do not play roles in cell signalization. Therefore, the preparation of this type of ceramides was studied in this work. Another reason to deal with 6- hydroxysfingosine was its unavailability on the market of chemical substances. Thus, the substance for further study was prepared. Synthesis of 6-hydroxysphingosine: first, commercially...
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