The role of platelet-activating factor in the pathogenesis of gastrointestinal disease

Travis, Simon

doi:10.1016/0952-3278(94)90092-2

Cited by 11 publications

(3 citation statements)

References 88 publications

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“…The PAF antagonist activity exerted by UR‐12715 upon release in the colonic lumen or even by the conjugate itself, would seem to play a key role counteracting the different deleterious effects that have been ascribed to PAF in these intestinal pathologies. ( Eliakim et al ., 1988 ; Travis & Jewell, 1994b ; Wardle et al ., 1996 ). For this reason, the inhibition of the effects exerted by this lipid mediator by specific antagonists can be useful in the management of these intestinal conditions, as has been demonstrated in the present study and was previously proposed for another PAF antangonist, BN52021, which was effective in the same model of intestinal inflammation ( Wallace et al ., 1989 ).…”

Section: Discussionmentioning

confidence: 99%

Intestinal anti‐inflammatory activity of UR‐12746, a novel 5‐ASA conjugate, on acute and chronic experimental colitis in the rat

Gálvez

Garrido

Merlos

et al. 2000

British J Pharmacology

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The present study was undertaken to investigate the intestinal anti‐inflammatory effects of UR‐12746 on the acute and chronic stages of a trinitrobenzene sulphonic acid (TNBS) experimental model of inflammatory bowel disease (IBD) in the rat. UR‐12746 is a novel, locally‐acting compound which combines, through an azo bond, 5‐aminosalicylic (5‐ASA) and UR‐12715, a potent platelet activating factor (PAF)‐antagonist. UR‐12746 oral pretreatment of colitic rats (50 and 100 mg kg−1) reduced acute colonic damage when evaluated 2 days after colonic insult. Postreatment for 4 weeks with UR‐12746 (50 and 100 mg kg−1) resulted in a faster recovery of the damaged colonic mucosa, which was macroscopically significant from the third week. The intestinal anti‐inflammatory effect of UR‐12746 was associated with a decrease in leukocyte infiltration in the colonic mucosa, which was evidenced both biochemically, by a reduction in myeloperoxidase activity, and histologically, by a lower leukocyte count after morphometric analysis. This effect was higher than that seen with sulphasalazine, when assayed at the same doses and in the same experimental conditions. Several mechanisms can be involved in the beneficial effects showed by UR‐12746: inhibition of leukotriene B4 synthesis in the inflamed colon, improvement of the altered colonic oxidative status, and reduction of colonic interleukin‐1β production. The results suggest that the intestinal anti‐inflammatory activity of UR‐12746 can be attributed to the additive effects exerted by 5‐ASA and UR‐12715, the PAF antagonist compound, that are released in the colonic lumen after reduction of the azo bond by the intestinal bacteria. British Journal of Pharmacology (2000) 130, 1949–1959; doi:

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Section: Discussionmentioning

confidence: 99%

Intestinal anti‐inflammatory activity of UR‐12746, a novel 5‐ASA conjugate, on acute and chronic experimental colitis in the rat

Gálvez

Garrido

Merlos

et al. 2000

British J Pharmacology

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“…Such direct and indirect actions contribute to the initiation and amplification of inflammatory process, including that of IBD . In fact, the colonic mucosa from patients with ulcerative colitis or Crohn's disease has been shown to produce higher levels of PAF than normal mucosa. , Moreover, treatment with glucocorticoids effectively reduces PAF levels in colonic mucosa . The objective of the present work was to synthesize aromatic amines B with potent PAF antagonist activity and prepare the corresponding azo derivative A of 5-ASA.…”

mentioning

confidence: 97%

“…7,8 Moreover, treatment with glucocorticoids effectively reduces PAF levels in colonic mucosa. 9 The objective of the present work was to synthesize aromatic amines B with potent PAF antagonist activity and prepare the corresponding azo derivative A of 5-ASA. Ideal pharmacokinetic properties of these compounds would comprise negligible systemic absorption of A, a high level of azo cleavage and also low absorption of B in the colon.…”

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confidence: 99%

Novel Azo Derivatives as Prodrugs of 5-Aminosalicylic Acid and Amino Derivatives with Potent Platelet Activating Factor Antagonist Activity

et al. 2001

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This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.

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Injurious and Protective Mechanisms in the Gut

Hsueh

Tan

et al. 1997

Advances in Experimental Medicine and Biology

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The role of platelet-activating factor in the pathogenesis of gastrointestinal disease

Cited by 11 publications

References 88 publications

Intestinal anti‐inflammatory activity of UR‐12746, a novel 5‐ASA conjugate, on acute and chronic experimental colitis in the rat

Intestinal anti‐inflammatory activity of UR‐12746, a novel 5‐ASA conjugate, on acute and chronic experimental colitis in the rat

Novel Azo Derivatives as Prodrugs of 5-Aminosalicylic Acid and Amino Derivatives with Potent Platelet Activating Factor Antagonist Activity

Injurious and Protective Mechanisms in the Gut

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