Abstract
BackgroundIntroduced 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.MethodologyThe 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 (14CO2 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 FindingsThere 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). Conclusions5-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.
Highlights
There are increasingly compelling data that all [9,10] or some of IBD may be caused by a single infectious agent Mycobacterium avium subspecies paratuberculosis (MAP.) [9,10,11,12,13] (& See [14] for review.) We have shown that two agents, methotrexate and 6-mercaptopurine (6-MP) [10], presumed to have ‘‘immunomodulatory’’ actions in IBD, [15,16] are potent antiMAP antibiotics
In this study we test the hypothesis that the ‘‘anti-inflammatory’’ action of 5-ASA and/or sulfapyridine could be due to one or both of sulfasalazine’s components acting as an antiMAP antibiotic(s.) If correct the ‘‘anti-inflammatory’’ effect would represent a normal, secondary, physiological response as the causative MAP infection was controlled by antiMAP antibiotic action
Either as results for an individual mycobacterial strain (Figures 1 & 2) or as a comparison of the effect of each agent tested on all four mycobacterial strains in Tabular form, where inhibition is expressed as %2DcGI, and enhancement as % +DcGI (Tables 1– 5.) Tables 1 & 2 are the experimental controls; Table 1 = the positive control methotrexate & Table 2 = the negative control sulfasalazine
Summary
In 1942 sulfasalazine (‘‘Salazopyrin’’) was introduced into clinical practice for ulcerative colitis. [1] Sulfasalazine has become, because of empirically observed clinical efficacy, ‘‘the most common medicine used to treat ‘‘Inflammatory’’ Bowel Disease (IBD) [2] with greatest efficacy in ulcerative colitis. [3,4,5]Sulfasalazine is a conjugate of sulfapyridine and 5- aminosalicylic acid (5-ASA.) It is cleaved into its two component molecules following ingestion. [2] The sulfapyridine moiety [(2-(p aminobenzenesulphonamido) pyridine] is an acknowledged antibiotic. [6,7] prevailing medical dogma concludes that ‘‘it is unlikely that (sulfasalazine’s) antibacterial activity accounts for its clinical efficacy.’’ [2] In 1977, a two-week study on ulcerative proctitis, compared 5-ASA to sulfapyridine. We suggested that the decreases in proinflammatory cytokines in IBD ‘‘immunomodulatory’’ therapy might reflect a normal, secondary, physiological response, as the instigating MAP infection was effectively treated. 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.) 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 conclude that 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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