Colonic Azodisalicylate Metabolism Determined by In Vivo Dialysis in Healthy Volunteers and Patients With Ulcerative Colitis

Lauritsen, K; Hansen, J.P. Hart; Ryde, M.; Rask-Madsen, J

doi:10.1016/s0016-5085(84)80164-x

Cited by 132 publications

(18 citation statements)

References 29 publications

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“…23 The clinical relevance of these findings is supported by the fact that the IC 50 of these actions are in the same (mm) concentration range or even one or two orders of magnitude below the free mesalazine concentrations found intraluminally and intramucosally in IBD patients receiving mesalazine maintenance treatment (7.0-14.0 mm). 24 An attractive hypothesis for the mesalazine ⁄ NSAID mode of action in this context relates not to COX inhibition itself, but rather the accumulation of arachidonic acid, which may be the decisive antiproliferative mechanism: arachidonic acid activates alkaline sphingomyelinase, which leads to increased ceramide production with activation of caspases and other apoptotic reactions. A hypothesis linking COX-dependent and COXindependent inhibitory mechanisms together is based on the peroxisome proliferator-activated receptor d (PPARd) system as a common pathway for both inflammatory (COX-dependent) and non-inflammatory (COX-independent) driven carcinogenesis.…”

Section: Mechanisms Of the Anti-proliferative Action Of Mesalazine: Cmentioning

confidence: 99%

Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease

Allgayer

2003

Aliment Pharmacol Ther

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Summary A series of epidemiological, experimental and preliminary clinical trials strongly suggest that mesalazine or 5‐aminosalicyclic acid (5‐ASA) may have antineoplastic and potentially prophylactic chemopreventive properties. It is assumed that mesalazine may have similar genetic and molecular targets as nonsteroidal anti‐inflammatory drugs (NSAIDs), which is further supported by its close similarity with aspirin, differing only in its structure by the presence of an amino group at position 5 of the benzene ring. The putative chemopreventive actions include the inhibition of inflammatory cascades and/or reactions involved in cell growth and proliferation, such as cyclo‐oxygenase (COX‐1 and COX‐2), which regulate cell proliferation through the formation of prostaglandins; lipoxygenase; nuclear factor κB (NFκB), responsible for the subsequent expression of pro‐inflammatory molecules; MAP kinases and Bcl‐2, as well as the activation of apoptotic processes, such as the stimulation of intestinal sphingomyelinase. The peroxisome‐proliferator‐activated receptor δ (PPARδ), which also regulates gene transcription, is thought to play a role in both inflammatory and non‐inflammatory driven carcinogenesis. This may be another significant target. It is hypothesized that 5‐ASAs may prevent the enhancing effect of prostaglandins on PPARδ binding to DNA by its COX inhibitory properties, decreasing proliferation of colorectal mucosal cells in non‐inflammatory bowel disease patients with sporadic polyps of the large bowel.

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Section: Mechanisms Of the Anti-proliferative Action Of Mesalazine: Cmentioning

confidence: 99%

Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease

Allgayer

2003

Aliment Pharmacol Ther

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“…This contrasts with drugs which are delivered to the colon for topical action, such as the various oral delayed-release formulations of 5-aminosalicylic acid, where the luminal extracellular¯uid drug concentration is derived largely from enteric delivery. 6 Rectal dialysis should also be suitable for sampling such drugs. The procedure of rectal dialysis was well tolerated by all subjects and no adverse events occurred.…”

Section: Discussionmentioning

confidence: 99%

“…to sample the faecal water for content of electrolytes, 4 soluble mediators of in¯ammation 5 and drugs. 6 In contrast to dialysis of faeces where dialysis bags are swallowed and collected in the stool, dialysis of the rectum samples the luminal extracellular¯uid of the lower colon only, by per rectum placement of a dialysis bag into the empty rectum. This technique has been used by a number of investigators to measure rectal concentrations of endogenously occurring compounds.…”

Section: Introductionmentioning

confidence: 99%

Dialysis of the rectum for sampling drug concentrations in the luminal extracellular fluid of the gut: technique and precision

Egan¹,

Sandborn²,

Mays

et al. 1998

Aliment Pharmacol Ther

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A fundamental principle of pharmacology is that a relationship exists between a drug's action and its concentration at the site of that action. Pharmacokinetic studies attempt to quantify this relationship by measuring the concentration of the drug in an accessible body¯uid. Traditionally, the body¯uids most conveniently sampled for this purpose are blood, plasma, urine and cerebrospinal¯uid. In the study of drugs active in the alimentary tract, it may be useful to measure their concentrations at the site of action.Sampling methods include biopsy of the intestinal mucosa to measure a drug's tissue concentration, 1, 2 but this technique requires endoscopy, with its attendant risks, the amount of tissue obtained is small and mucosal oedema from in¯ammation may dilute the local tissue concentration. Analysis of drug concentration in stool, speci®cally the faecal water component of stool, is also possible, but variations in the volume and hydration of stool limit the precision of this technique.In this report, we propose and validate an alternative technique for sampling the luminal extracellular¯uid of the large intestine for quantitative drug analyses, dialysis of the rectum. This procedure is a derivation of the technique of in vivo dialysis of faeces, introduced by Wrong in the 1960s. 3, 4 Dialysis of faeces has been used SUMMARY Background: It is useful to measure the luminal concentration of drugs which act in the gut. Dialysis of the rectum has not previously been used or validated for this purpose. Aim: To determine the precision of rectal dialysis for measuring rectal drug concentrations. Methods: To establish the duration of dialysis required to approach equilibrium, the rate of methotrexate diffusion into dialysis bags was ®rst determined in vitro. The precision of rectal dialysis for sampling the methotrexate concentration of colonic lumen extracellular¯uid was determined in seven subjects who underwent two consecutive dialysis procedures. Subjects treated with subcutaneous methotrexate for refractory in¯ammatory bowel disease were studied.

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“…In the extrapolation to faecal-concentrations per gram wet weight, however, factual concentrations may be overestimated considerably in solid faeces. In studies using dialysis bags (66,68,71), the determination of faecal concentrations (per gram wet weight) as well as recovery the analytical error by applying a standard water-fraction in calculations will be proportional to the difference between the standard and the true water-phase in the individual samples.…”

Section: V2 Methods Of the Present Studiesmentioning

confidence: 99%

Intestinal Fate of 5‐aminosalicylic Acid: Regional and Systemic Kinetic Studies in Relation to Inflammatory Bowel Disease

Bondesen¹

1997

Pharmacology & Toxicology

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Colonic Azodisalicylate Metabolism Determined by In Vivo Dialysis in Healthy Volunteers and Patients With Ulcerative Colitis

Cited by 132 publications

References 29 publications

Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease

Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease

Dialysis of the rectum for sampling drug concentrations in the luminal extracellular fluid of the gut: technique and precision

Intestinal Fate of 5‐aminosalicylic Acid: Regional and Systemic Kinetic Studies in Relation to Inflammatory Bowel Disease

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