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Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis
Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be admini...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834954/ https://www.ncbi.nlm.nih.gov/pubmed/24300448 http://dx.doi.org/10.3390/pharmaceutics5020232 |
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author | Lau, Wing Man Heard, Charles M. White, Alex W. |
author_facet | Lau, Wing Man Heard, Charles M. White, Alex W. |
author_sort | Lau, Wing Man |
collection | PubMed |
description | Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, V(max) = 10.3 µM·min(−1) and K(m) = 65.1 µM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis. |
format | Online Article Text |
id | pubmed-3834954 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-38349542013-11-21 Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis Lau, Wing Man Heard, Charles M. White, Alex W. Pharmaceutics Article Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, V(max) = 10.3 µM·min(−1) and K(m) = 65.1 µM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis. MDPI 2013-04-17 /pmc/articles/PMC3834954/ /pubmed/24300448 http://dx.doi.org/10.3390/pharmaceutics5020232 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Lau, Wing Man Heard, Charles M. White, Alex W. Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title | Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title_full | Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title_fullStr | Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title_full_unstemmed | Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title_short | Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis |
title_sort | design, synthesis and in vitro degradation of a novel co-drug for the treatment of psoriasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834954/ https://www.ncbi.nlm.nih.gov/pubmed/24300448 http://dx.doi.org/10.3390/pharmaceutics5020232 |
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