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On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis

BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat “inflammatory” bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratu...

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Autores principales: Greenstein, Robert J., Su, Liya, Shahidi, Azra, Brown, Sheldon T.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885215/
https://www.ncbi.nlm.nih.gov/pubmed/17565369
http://dx.doi.org/10.1371/journal.pone.0000516
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author Greenstein, Robert J.
Su, Liya
Shahidi, Azra
Brown, Sheldon T.
author_facet Greenstein, Robert J.
Su, Liya
Shahidi, Azra
Brown, Sheldon T.
author_sort Greenstein, Robert J.
collection PubMed
description BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat “inflammatory” bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC®) detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (%−ΔcGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%−ΔcGI at 64 µg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%−ΔcGI at 4 µg/ml) is as effective as methotrexate, our positive control (88%−ΔcGI at 4 µg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups.
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spelling pubmed-18852152007-06-13 On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis Greenstein, Robert J. Su, Liya Shahidi, Azra Brown, Sheldon T. PLoS One Research Article BACKGROUND: Introduced in 1942, sulfasalazine (a conjugate of 5-aminosalicylic acid (5-ASA) and sulfapyridine) is the most prescribed medication used to treat “inflammatory” bowel disease (IBD.) Although controversial, there are increasingly compelling data that Mycobacterium avium subspecies paratuberculosis (MAP) may be an etiological agent in some or all of IBD. We have shown that two other agents used in the therapy of IBD (methotrexate and 6-MP) profoundly inhibit MAP growth. We concluded that their most plausible mechanism of action is as antiMAP antibiotics. We herein hypothesize that the mechanism of action of 5-ASA and/or sulfapyridine may also simply be to inhibit MAP growth. METHODOLOGY: The effect on MAP growth kinetics by sulfasalazine and its components were evaluated in bacterial culture of two strains each of MAP and M. avium, using a radiometric ((14)CO(2) BACTEC®) detection system that quantifies mycobacterial growth as arbitrary “growth index units” (GI). Efficacy data are presented as “percent decrease in cumulative GI” (%−ΔcGI). PRINCIPAL FINDINGS: There are disparate responses to 5-ASA and sulfapyridine in the two subspecies. Against MAP, 5-ASA is inhibitory in a dose-dependent manner (MAP ATCC 19698 46%−ΔcGI at 64 µg/ml), whereas sulfapyridine has virtually no effect. In contrast, against M. avium ATCC 25291, 5-ASA has no effect, whereas sulfapyridine (88%−ΔcGI at 4 µg/ml) is as effective as methotrexate, our positive control (88%−ΔcGI at 4 µg/ml). CONCLUSIONS: 5-ASA inhibits MAP growth in culture. We posit that, unknowingly, the medical profession has been treating MAP infections since sulfasalazine's introduction in 1942. These observations may explain, in part, why MAP has not previously been identified as a human pathogen. We conclude that henceforth in clinical trials evaluating antiMAP agents in IBD, if considered ethical, the use of 5-ASA (as well as methotrexate and 6-MP) should be excluded from control groups. Public Library of Science 2007-06-13 /pmc/articles/PMC1885215/ /pubmed/17565369 http://dx.doi.org/10.1371/journal.pone.0000516 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Greenstein, Robert J.
Su, Liya
Shahidi, Azra
Brown, Sheldon T.
On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title_full On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title_fullStr On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title_full_unstemmed On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title_short On the Action of 5-Amino-Salicylic Acid and Sulfapyridine on M. avium including Subspecies paratuberculosis
title_sort on the action of 5-amino-salicylic acid and sulfapyridine on m. avium including subspecies paratuberculosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885215/
https://www.ncbi.nlm.nih.gov/pubmed/17565369
http://dx.doi.org/10.1371/journal.pone.0000516
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