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Effect of pH on transdermal delivery of adefovir
Lorencová, Kateřina ; Vávrová, Kateřina (advisor) ; Doležal, Pavel (referee)
Adefovir (PMEA) belong to the group of acyclic nucleoside analogues exhibiting various biological (e.g. antiviral, cytostatic, antiparasitic, immunomodu-latory) activities. Its prodrug adefovir dipivoxil (PMEAd) has recently been approved for the treatment of chronic hepatitis B. The aim of this work was to study permeation properties of 2% PMEA in vitro in the broad spectrum of pH using different vehicles with or within presence of permeation enhancers. We also evaluated penetration of PMEA into the porcine skin. Transdermal permeation of 2% PMEA was studied in vitro using the Franz diffusion cell and full-thickness porcine skin. Tris, phosphate buffer (PB) and water (only for pH 3.4) were used as vehicles, pH was in range from 3.4 to 8.8. 1% Dodecyl 6-dimethylaminohexanoat (DDAK) and 1% Transkarbam 12 (5-dodecyloxycarbonyl) pentylammonium-5-(dodecyloxycarbonyl) pentylcarbamate (T12)) were used as permeation enhancers. The flux values were 1.8 ± 0.5, 0.2 ± 0.1, and 0.7 ± 0.4 μg/cm2 /h from aqueous, PB and Tris donor samples at pH 3.4. The respective skin concentrations at 48 h were 294 ± 75, 110 ± 39, and 178 ± 71 μg/g from these vehicles. The flux values of 2% PMEA in PB were from 0.2 ± 0.1 to 2.7 ± 1.32, and from 9.4 ± 4.3 to 26.9 ± 3.4 μg/cm2 /h without and with the presence of 1% DDAK,...
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The physico-chemical characterization of prospective transdermal absorption enhancers.
Vavrysová, Helena ; Zbytovská, Jarmila (advisor) ; Vávrová, Kateřina (referee)
THE PHYSIOCHEMICAL CHARACTERISATION OF POSSIBLE ENHANCERS FOR ABSORPTION The work is deal with studies of lipid and characterisation of the thermotopic behaviour of selected possible enhancers for transdermal absorption. The thermotropic behaviour was observed by combination DSC and IR spectroscopy of five synthetic compounds with similar structure as skin ceramides. We can deduce that all studied enhancers are highly ordered structures with high numer of trans conformers and triclinical lipid chain packing. With increased temperatur growth number of gauche conformers and increase fluidity of lipid chain. At the same time dissapear hydrogen bounds which form on the polar heads between lipid chains. Temperature differencies of phase transitions of measuring compounds is considerable. It can be caused insuficient heating of ATR crystal but exists linear dependence of correlation. With increased temperature growth measurement error. This dependence can be used for other measurements.
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Synthesis of novel cardioprotective iron chelators
Hrušková, Kateřina ; Roh, Jaroslav (referee) ; Vávrová, Kateřina (advisor)
Oxidative stress participates in patophysiology of many serious cardiovascular diseases. Free intracellular iron occurs as a catalyst of Haber-Weiss and Fenton reaction between superoxides and peroxides increasing the formation of highly toxic hydroxyl radicals, which cause cell damage. Iron chelators diminish the pool of free iron and thus become perspective agents in therapy of various diseases, e.g. anthracycline-induced cardiotoxicity. Aroylhydrazones group, such as salicylaldehyde-isonicotinoylhydrazone (SIH), appear to be highly efficient chelators. Unfortunately, pharmacokinetic studies focused on these compounds revealed their low stability in plasma. Therefore, I synthesised a series of SIH analogs in order to increase their stability together with preserving the ability to chelate free intracellular iron and to define their structure-activity relationships. A basic hypothesis in design of the novel chelators was using substituted ketone instead of aldehyde, leading potentially to an enhanced stability of hydrazone bond. SIH Two different methods were used during the reactions, a conventional heating in an oil bath and heating in a microwave reactor. The latter caused a significant shortening of the reaction time. In vitro studies of novel compounds showed their higher stability in plasma,...
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Synthesis of ceramide analogs with various sphingosine length and evaluation of their effects on the skin barrier
Školová, Barbora ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides are a complex group of lipids, naturally occurring in the uppermost layer of the epidermis, in the stratum corneum (SC). They constitute a major component of extracellular matrix and they are responsible for the skin barrier properties. Diseases such as atopic dermatitis or psoriasis are associated with the decline in content and changes in the composition of ceramides, which lead to the reduction in the protective functions of the skin. Although the importance of ceramides is known, the relationship between their structure and effect on the barrier function is not yet fully elucidated. Earlier studies indicate that the length of ceramide acyl chain affects the skin permeability. It appears that ceramides with short acyl lose the protective properties. First, I have prepared a series of analogues of ceramides with fifteen carbon atoms chain in the sphingosine part and the acyl part of a length of 2, 4 and 6 carbons. Starting substance of the synthesis was N-protected L-serine methyl ester, which was further protected by the formation of a cyclic acetal and subjected to the reduction of the ester to aldehyde. The resulting aldehyde reacted with 1-alcynide in the presence of HMPA. The triple bond was subsequently reduced to a trans-double bond by lithium in ethylamine. After deprotection of...
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Ceramides and Dimethylamino Acid Derivatives as Skin Barrier Modulators
Novotný, Jakub ; Vávrová, Kateřina (advisor) ; Sedlák, Miloš (referee) ; Doležal, Pavel (referee)
The purpose of this work is to contribute to the understanding of the structure-activity relationships and behavior of the skin ceramides and transdermal penetration enhancers based on dimethylamino acid esters. First two chapters provide a theoretical background for understanding the main principles of transdermal drug delivery as well as composition and function of stratum corneum barrier. The experimental work is presented in the form of individual publications in chapters three to five. The first chapter describes transport routes through the human skin and gives an overview of enhancers of transdermal permeation with main accent on their chemical structure, mechanism of action, interaction with stratum corneum components and advantages and drawbacks of their use. The second chapter brings more detailed information on the specific content and composition of stratum corneum. The main attention is paid to the ceramides - a complex group of lipids that play a crucial role as cell signaling molecules and skin barrier constituents. In the skin, these sphingolipids form a major part of the stratum corneum intercellular lipid matrix, which is the barrier for penetration of most compounds. The development of such a protective layer was a critical step in the evolution of life on a dry land. Moreover,...
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Effect of ceramide acyl chain length on the skin permeabillity
Lorenc, Petr ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Ceramides that are present in stratum corneum (SC), the uppermost layer of the skin, are responsible for skin barrier function and thus for its permeability for drugs. Their role in the formation of skin barrier has been widely described; however, up to now, their structure-activity relationships have not been fully revealed. Previous studies suggested, that the ceramide acyl chain length is a key factor for the permeability of the skin barrier. The aim of this work was to study the influence of the length of ceramide acyl chain on the permeability of the skin barrier using short ceramides, sphingosine, phytoshingosine and ceramide 2 (NS). Short ceramide analogues contained sphingosine with 18 carbon atoms and the acyl chain ranging from 2 to 18 carbon atoms. Their influence on skin permeability was tested in vitro in Franz diffusion cells on dermatomed porcine skin using two model drugs - theophylline (TH) and indomethacin (IND). Donor samples were prepared as 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND with addition of 1% (w/v) ceramide in 60% (v/v) propylene glycol. Negative samples for the comparison of the fluxes and the drug concentrations contained 5% (w/v) suspension of TH and 2.5% (w/v) suspension of IND propylene glycol without the addition of ceramide. Phosphate buffer...
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Monosubstituted 5,6-dihydro-2H-pyran-2-ones. Natural occurence, biological activity and synthetic approaches.
Bešťák, Petr ; Špulák, Marcel (advisor) ; Vávrová, Kateřina (referee)
5,6-Dihydro-2H-pyran-2-ones are naturally occurring substances, very widely distributed in the nature. Their biological activities have been known for a long time. In last few decades, along with the development of instrumental equipment and synthetic skills of modern chemistry, systematic research and structure-activity relationship's of these compounds became a challenging task. This review embraces monosubstituted pentenolides, mostly those, substituted in the 6-position. Furthermore, it reveals the possible reason for the generally exclusive natural occurrence of the 6-substituted 5,6-dihydro-2H-pyran-2-ones on the opposite to other - 3, 4 and 5-substituted analogues. This review describes most of known naturally occurring monosubstituted pentenolides, including their structure and confirmed or suspected biological activities. Synthetic approaches to pentenolides have been considered and collected.
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Synthesis of transdermal permeation enhancers based on piperidine carboxylic acids
Fratričová, Veronika ; Vávrová, Kateřina (advisor) ; Hrabálek, Alexandr (referee)
Transdermal permeation enhancers are chemical compounds, which promote drug absorption through the skin via the barrier resistance decrease. The model structure was molecule of transkarbam 12. I have synthesized these compounds: 2-(decyloxycarbonyl)piperidinium bromide 2-(dodecyloxycarbonyl)piperidinium bromide 1-acetylpiperidine-2-carboxylic acid decyl ester 1-acetylpiperidine-2-carboxylic acid dodecyl ester (R)-N -acetylpiperidin-2-carboxylic acid decyl ester (R)-N -acetylpiperidin-2-carboxylic acid dodecyl ester (R)-N -acetylpiperidin-3-carboxylic acid decyl ester (R)-N -acetylpiperidin-3-carboxylic acid dodecyl ester 2-(decyloxycarbonyl)piperidinium 2-(decyloxycarbonyl)piperidine-1-carbamate 2-(dodecyloxycarbonyl)piperidinium 2-(dodecyloxycarbonyl)piperidine-1-carbamate Transdermal permeation-enhancing activity of the prepared compounds was evaluated on the porcine skin in the Franz diffusion cells using theophylline as the model drug. The enhancement ratio values were compared with the results of structurally related compounds synthesized in the previous diploma theses. The results showed that the least active substances were the hydrobromides, N-acetylderivatives were more active, comparable with model enhancer transkarbam 12. No significant difference between racemates and (R)-izomers of N-...
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