Effects of sulphasalazine and disodium azodisalicylate on colonic PGE2 concentrations determined by equilibrium in vivo dialysis of faeces in patients with ulcerative colitis and healthy controls.

Abstract

SUMMARYThe role of arachidonic acid metabolites and the mode of action of 5-aminosalicylic acid, the active moiety of sulphasalazine and disodium azodisalicylate, in ulcerative colitis remain obscure. Therefore, experiments were performed in which the effects of medication on immunoreactive prostaglandin (PG) E2 concentrations in free faecal water were assessed using the equilibrium in vivo dialysis of faeces. Colonic PGE2 concentrations in patients with active ulcerative colitis (n= 11) ranged from 2035-18 000 pg/ml to be compared with a range of 103-188 pg/ml in healthy volunteers (n=10; p<0.001). In all healthy volunteers PGE2 concentrations decreased slightly (p<005) after disodium azodisalicylate intake 2 g/day, whereas low dose disodium azodisalicylate (0.25 g/day) caused no change. In patients with ulcerative colitis in complete clinical, sigmoidoscopic, and histologic remission withdrawal of sulphasalazine (2 g/day; n=6) increased PGE2 concentrations to values above normal levels (p<005) which returned to pretrial values (p<005) on disodium azodisalicylate (2 g/day; n=7). In conclusion, increased PGE2 in free faecal water indicates an abnormality in the colonic mucosa, even in the absence of conventional signs of inflammation. We could not confirm the hypothesis that sulphasalazine and 5-aminosalicylic acid exert their therapeutic effect through promotion of endogenous cytoprotective prostaglandins. In contrast, the observation that raised PGE2 concentrations were normalised by disodium azodisalicylate in patients with inactive ulcerative colitis suggests that subclinical disease activity was decreased by 5-aminosalicylic acid.Both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism have been implicated in the pathogenesis of ulcerative colitis. The findings of increased amounts of prostanoids in faeces and rectal mucosa of patients with ulcerative colitisl-3 provided the hypothesis that prostaglandins may mediate the inflammatory response. The therapeutic effect of 5-aminosalicylic acid which is proved to be the major, though not necessarily the only active component of sulphasalazine,4 may be related to the anti-inflammatory activity of the substance which is a salicylate and a weak prostaglandin

The antiinflammatory moiety of sulfasalazine, 5-aminosalicylic acid, is a radical scavenger

“…In contrast, oral administration of 5-ASA itself is ineffective, since the drug is then rapidly absorbed and inactivated by acetylation [10]. Enhanced eicosanoid release in colonic mucosa of patients with chronic inflammatory bowel disease [11,12] may be related to high levels of reactive oxygen species [13]. Reports on lipoxygenase inhibition by 5-ASA may therefore partly reflect antioxidant activity, a phenomenon also thought to explain leukotriene synthesis inhibition by NDGA [14].…”

Newly Developed Alternatives to Sulphasalazine for Use in Inflammatory Bowel Disease

“…These preparations are needed as 5-ASA is readily absorbed by the small intestine and their breakdown has been examined to dem onstrate the rate of release of 5-ASA. Both preparations have been validated and found to release the major part of the 5-ASA in the large intestine [34,36], In healthy volunteers taking 1.5-2.4 g of 5-ASA daily, plasma con centrations of 1-3 |ig/ml, nearly all n-acetyl-5-ASA, were obtained, comparable to those obtained when an equivalent dose of sulpha salazine is taken [33,37,38], When the sus tained release preparation of 5-ASA was given to ileostomists about 65% appeared in the ileostomy effluent [34]: the majority of the resin-coated tablets have been shown to break down in the terminal ileum and colon [35,36], The pattern of faecal and urinary excretion of 5-ASA from these two prepara tions and from sulphasalazine is similar. In healthy volunteers 25-55% of oral 5-ASA appeared in the urine, mostly as acctyl-5-ASA, and 18-42% appears after oral sulpha salazine [33,[38][39][40].…”

“…Changes occur in the faecal flora in patients with inflammatory bowel disease, which may be beneficial [30], Whether 5-ASA shares these effects has not been established. However, both 5-ASA and sulphasalazine have similar effects on prostaglandin synthesis [31][32][33].…”

Role of Eicosanoids in Diarrheal Diseases

“…Evidence against this hypothesis is the demonstration of abnormally high luminal PGE: levels as determined by equilibrium in vivo dialysis of feces in patients with untreated ulcerative colitis in complete remission [32].…”

“…and LTB4 us ing the same technique [38] or the original method of in vivo dialysis of feces [32], These techniques have demonstrated that positive correlations exist between the lumi nal concentration of PGE2 or LTB4 and dis ease activity judged by clinical, endoscopic, or histologic gradings [38. 39], The luminal concentrations of eicosanoids are always raised in active disease, but decrease towards upper normal limits in inactive disease.…”