PURPOSE: In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. METHODS: The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. RESULTS: The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. CONCLUSIONS: By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

• MeSH
• 2-aminopurin aplikace a dávkování   analogy a deriváty   chemie   MeSH
• antivirové látky aplikace a dávkování   chemie   MeSH
• aplikace kožní MeSH
• kožní absorpce účinky léků   fyziologie   MeSH
• lidé MeSH
• liposomy MeSH
• orgánové kultury - kultivační techniky MeSH
• prekurzory léčiv aplikace a dávkování   chemie   MeSH
• systémy cílené aplikace léků metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-aminopurin MeSH
• 2,6-diaminopurine MeSH Prohlížeč
• antivirové látky MeSH
• liposomy MeSH
• prekurzory léčiv MeSH

PURPOSE: Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP. METHODS: In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin. RESULTS: Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm(2)/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed. CONCLUSIONS: Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.

• MeSH
• adenin aplikace a dávkování   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• antivirové látky aplikace a dávkování   MeSH
• aplikace kožní MeSH
• dimethylaminy MeSH
• dodekanol MeSH
• kapronáty metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• methylaminy metabolismus   MeSH
• organofosfonáty aplikace a dávkování   MeSH
• permeabilita MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• antitumorózní látky MeSH
• antivirové látky MeSH
• dimethylaminy MeSH
• dodecyl 6-(dimethylamino)hexanoate MeSH Prohlížeč
• dodekanol MeSH
• kapronáty MeSH
• methylaminy MeSH
• N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine MeSH Prohlížeč
• organofosfonáty MeSH

PURPOSE: Series of N,N-dimethylamino acid esters was synthesized to study their transdermal permeation-enhancing potency, biodegradability and reversibility of action. Effects of chirality, linking chain length and polyfluorination were investigated. MATERIALS AND METHODS: In vitro activities were evaluated using porcine skin and four model drugs-theophylline, hydrocortisone, adefovir and indomethacin. Biodegradability was determined using porcine esterase, reversibility was measured using electrical resistance. RESULTS: No differences in activity were found between (R), (S) and racemic dodecyl 2-(dimethylamino)propanoate (DDAIP). Substitution of hydrocarbon tail by fluorocarbon one resulted in loss of activity. Replacement of branched linking chain between nitrogen and ester of DDAIP by linear one markedly improved penetration-enhancing activity with optimum in 4-6C acid derivatives. Dodecyl 6-(dimethylamino)hexanoate (DDAK) was more potent than clinically used skin absorption enhancer DDAIP for theophylline (enhancement ratio of DDAK and DDAIP was 17.3 and 5.9, respectively), hydrocortisone (43.2 and 11.5) and adefovir (13.6 and 2.8), while DDAIP was better enhancer for indomethacin (8.7 and 22.8). DDAK was rapidly metabolized by porcine esterase, and displayed low acute toxicity. Electrical resistance of DDAK-treated skin barrier promptly recovered to control values. CONCLUSION: DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate for future research.

• MeSH
• adenin analogy a deriváty   metabolismus   MeSH
• alanin aplikace a dávkování   analogy a deriváty   chemická syntéza   farmakologie   MeSH
• aplikace kožní MeSH
• časové faktory MeSH
• chemie farmaceutická MeSH
• dimethylaminy MeSH
• dodekanol MeSH
• elektrická impedance MeSH
• esterasy metabolismus   MeSH
• halogenace MeSH
• hydrokortison metabolismus   MeSH
• hydrolýza MeSH
• indomethacin metabolismus   MeSH
• isomerie MeSH
• kapronáty aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• kožní absorpce účinky léků   MeSH
• kůže účinky léků   metabolismus   MeSH
• methylaminy aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• molekulární struktura MeSH
• nosiče léků MeSH
• organofosfonáty metabolismus   MeSH
• prasata MeSH
• příprava léků MeSH
• stabilita léku MeSH
• theofylin metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• alanin MeSH
• dimethylaminy MeSH
• dodecyl 2-(N,N-dimethylamino)propionate MeSH Prohlížeč
• dodecyl 6-(dimethylamino)hexanoate MeSH Prohlížeč
• dodekanol MeSH
• esterasy MeSH
• hydrokortison MeSH
• indomethacin MeSH
• kapronáty MeSH
• methylaminy MeSH
• nosiče léků MeSH
• organofosfonáty MeSH
• theofylin MeSH