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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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Synthesis of novel cardioprotective iron chelators
Hrušková, Kateřina ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
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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Synthesis and study of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoic acid derivatives as transdermal permeation enhancers
Kučera, Ondřej ; Vávrová, Kateřina (advisor) ; Nováková, Veronika (referee)
Ondřej Kučera Charles University in Prague, Faculty of Pharmacy in Hradec Králové Synthesis and study of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)hexanoic acid derivatives as transdermal permeation enhancers Transdermal permeation enhancers are used to increase absorption of drugs through skin or, more importantly, through the stratum corneum, which is the uppermost layer of the skin. Mechanism of action of enhancers is not fully understood. In general the most active enhancers consist of hydrophilic and hydrophobic parts. In this work, we prepared and studied fluorescent permeation enhancers. Fluorescent dye NBD (7-nitrobenzo[c][1,2,5]oxadiazol) is fairly hydrophilic, so we used it as a hydrophilic head of potential enhancers based on dodecyl 6- (dimethylamino)hexanoate (DDAK). Such fluorescent enhancers could help us understand more about the mechanism of action. It enables determination of this enhancer and imaging of its penetration pathways in the skin. We synthesized three esters of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)-hexanoic acid (NBD-acid) with ester-linked C8-C12 alkyls. 6-Aminocaproic acid reacted with 4-chloro- NBD and then with a series of alcohols to give us different lengths of alkyl chains. We applied these enhancers to human skin in Franz diffusion cells using two...
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Study of transdermal and dermal absorption of 2,6-diaminopurine acyclic nucleoside phosphonates
Diblíková, Denisa ; Vávrová, Kateřina (advisor) ; Zbytovská, Jarmila (referee)
Acyclic nucleoside phosphonates (ANP) are broad-spectrum antivirals highly effective against herpes-, retro- and hepadnaviruses. They also exhibit cytostatic, antiparasitic, immunomodulatory activities. Their transdermal delivery offers an attractive and advantageous route of administration, but is limited due to the polar character of their phosphonate moiety. The aim of this work was to study the possibility of both transdermal and dermal application of a series of 2,6-diaminopurine derivatives including (R)-PMPDAP and (S)-PMPDAP, (S)-HPMPDAP, (S)-8-azaHPMPDAP, cyclic (S)-HPMPDAP and lysolipid prodrugs, i.e., hexadecyloxypropyl (HDP) esters of (R)-HDP-PMPDAP and (S)-HDP- HPMPDAP. Ability of ANP to penetrate trough the skin by themselves is generally very low. For this reason the influence of permeation enhancer dodecylester of 6- (dimethylamino)hexanoic acid (DDAK) through and into human skin was investigated. The evaluation was performed in vitro by using Franz diffusion cells and human skin. The results of this work confirm that ANP (60 mM in 60 % propylene glycol) delivery through the skin is very low (flux 0.53-1.40 nmol/cm2 /h), except for the lysolipid prodrugs (R)-HDP-PMPDAP and (S)-HDP-HPMPDAP), which were not detected in the acceptor phase at all. 1 % DDAK enhanced transdermal flux of...
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Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine and study of its physicochemical properties
Valášková, Lenka ; Roh, Jaroslav (advisor) ; Vávrová, Kateřina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of inorganic and organic chemistry Candidate: Lenka Valášková Supervisor: PharmDr. Jaroslav Roh, PhD, Carine Deleuze-Masquefa Title of diploma thesis: Synthesis of 1-(3-methoxyphenyl)-N-methylimidazo[1,2- a]quinoxalin-4-amine and study of its physicochemical properties Melanoma is malign tumor usually located in the skin, mucous membranes or rarely in other parts of the organism. Every year the prevalence of this tumor is growing. Tumors which are detected in early stages can be successfully removed, but when metastasis appear treatment of this type of cancer is difficult. Some tumors (e.g. on problematic places such as on face) cannot be removed by surgery, even if they are soon detected. In these cases, topically administered anticancer drugs can be used. One of those substances is imiquimod (ALDARA® ; Figure 1), possesses antiviral, immunostimulating and cytotoxic activity. Limiting factor of this substance is its toxicity- it can be used only topically. The research group of prof. Pierre-Antoine Bonnet deals with the synthesis of imiquimod analogues. Synthesized molecules belong to three chemical groups, which differ in the orientation of imidazole moiety. Their lead structures, providing higher in vitro cytotoxic...
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Substituted benzoxazoles - synthesis and biological activity
Opálka, Lukáš ; Vinšová, Jarmila (advisor) ; Vávrová, Kateřina (referee)
There were 14 compounds prepaired, including 7 Schiff bases and 7 substitued benzoxazoles. The compounds were characterised by 1 H NMR, 13 C NMR, IR, TLC and by melting point. All the new compounds aren't described in Reaxys or in Chemical Abstracts, so they can be considered as original compounds. The reaction was done in two steps. First, the Schiff base was made by the condensation of proper aminophenol and benzaldehyde and in second step, the Schiff base was cyclized by lead (IV) acetate.
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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 ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties
Jandovská, Kateřina ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Jandovská, Kateřina: Synthesis of ceramide and dihydroceramide analogues and evaluation of their effects on the skin barrier properties. Ceramides belong to sphingolipids, their molecule is formed by a sphingoid base and long fatty acid. They are known not just as important second messengers playing a significant role in cell differentiation, proliferation and apoptosis, but also as essential part of functional skin barrier. Although these molecules are studied intensively, the exact effect of their structure on barrier function of the skin is poorly understood. The aim of my work was to study the effect of acyl chain length and stereochemistry on C3 of dihydroceramides (ceramides with single bond on C4) on the permeability of model membranes simulating the skin barrier. I have synthetized 3 ceramides with short acyl chain of 4 carbons (derived from dihydrosphingosine (dS), L-threo-dihydrosphingosine (L-dS) and L-threo-sphingosine (L-S)), and prepared model membranes of stratum corneum (SC) containing dihydroceramides with C2, C4, C6, C8 and C24 acyl chain length and stereoisomeres of C4-ceramides and C4-dihydroceramides as well. I have evaluated their electrical impedance and permeability for two model drugs. The effects of the prepared ceramides on the model membrane permeability were evaluated...
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Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers
Psík, Martin ; Vávrová, Kateřina (advisor) ; Roh, Jaroslav (referee)
Martin Psík Charles University in Prague, Faculty of Pharmacy in Hradec Králové 2015 Synthesis and study of deuterated and polyene analogs of selected transdermal permeation enhancers Transdermal drug delivery offers many advantages over traditional routes of administration. Main factor limiting permeation of the drug is barrier property of the skin especially its uppermost layer stratum corneum. One of the approaches to promote drug flux through SC uses permeation enhancers. Most permeation enhancers are not suitable for clinical use due to their toxicity or irritation potential. Interesting family of permeation enhancers are amino acid derivatives, in particular for their low toxicity. Very promising amino acid derivatives seem to be dodecyl 6-dimethylaminohexanoate (DDAK) and dodecyl (S)-N-acetylprolinate (L-Pro2). Their mechanism of action is not fully understood. The main goal of this diploma thesis was to contribute to the understanding of the behavior of these two transdermal permeation enhancers in the skin. In the first part of this thesis deuterated analogues of DDAK and Pro2 with deuterated dodecyl chains (previous studies show no difference between L- and D-Pro2, thus, we only used Pro2) were prepared and then their influence on the SC lipids and proteins were studied by infrared...
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