Najmuddin Banatwala  ( PMRC Research Centre, Jinnab Postgraduate Medical Centre, Karachi. )

Salazopyrin has been in use for over 4u years now and various clinical studies during the last two decades have proved its efficacy in the treatment of both ulcerative colitis and Crohn’s disease.
Salazopyrin is a conjugate of 5 amino salycylic acid and sulphapyridine, linked by an azo bond. About 1/3 of the drug is absorbed from the upper G.I. tract and usually less than 10% of the total administered dose is excreted unchanged in the urine. The remaining absorbed portion is excreted as such in the bile and along with non-absorbed portion reaches the distal small intestine and colon¹.
In the colon, bacterial reduction splits the drug into its two constituents.² Sulphapyridin is absorbed, partially metabolised and excreted in the urine, whereas 5 amino-salicylate remains largely in the colon, only a small portion being absorbed, and is probably the therapeutically active moiety of salazopyrin³.
Several studies including randomized controlled trials have shown marked improvement in the patients’s clinical condition and sigmoidoscopic appearances with salazopyrin compared to placebo and other drugs.^4-6 However in one study,⁷ steroid therapy was judged to be more prompt and overall more effective than that with salazopyrin, suggesting a combined treatment to be moreS effective. One group of investigators⁸  suggested early use of salazopyrin in patients with severe ulcerative colitis after a response to systemic steroids had been obtained.
Further studies have established a role of maintenance therapy with salazopyrin in ulcerative colitis.⁹ Subsequent studies^10-13 have convincingly shown a better prophylactic effect of salazopyrin as compared to high-fibre diet or mast cell stablisers such .as cromoglycate and it seems that Salazopyrin therapy continued beyond one year is likely to confer continued prophylaxis against relapse. The optimum dose for main­tenance therapy, which is effective and yet gives lesser side effects, has been determined to be 2 gms daily in divided doses.¹⁴
Several studies have suggested the usefulness of salazopyrin in the treatment of Crohn’s disease^15-17 and a controlled double blind study found 3 gm/day of salazopyrin to be significantly more effective than placebo in active Crohn’s disease.¹⁸ Subsequent studies confirmed these findings but no beneficial effect was noted in patients with ileitis alone¹⁹. Again salazopyrin was less effective than prednisone alone in active Crohn’s disease, ²⁰ and unlike the case in ulcerative colitis, it has not been shown to be of benefit in maintaining remission in Crohn’s disease¹⁹. A study which evaluated the prophylactic effect of salazopyrin post-operatively, did not find it to have a. significant beneficial effect in preventing recurrence of Crohn’s disease²¹
Metabolic studies of salazopyrin have indicated that 5-aminosalicylate may be the active moiety of the drug and that sulphapyridine is responsible for the drug’s toxicity. A study in which either salazopyrin, 5-aminosalicylate or sulphapyridine was administered as retention enemas in a blinded controlled fashion, over a 2 week period to patients. With active, mild to moderate ulcerative colitis, made the authors conclude that 5-aminosalicylate is the active component of salazopyrin.²²
In other studies, suppositories containing 5 aminosalicylate were found to be as effective as salazopyrin given either as a suppository or orally and was more effective than either sulphapyridine or placebo given similarly.²³ 5-amino-salicylate and salazopyrin enemas were effective in inducing clinical and sigmoidoscopic remission in patients with proctitis or left sided colitis.²⁴ A related agent-4-aminosalycylate also appears to be effective as an enema for treating distal colitis.²⁵
As enemas are a rather inconvenient form of treatment especially as maintenance therapy, preparations that could deliver intact 5-amino-salicylate to the lower intestine, as does salazopyrin, were sought. One such compound is disodium azodisalicylate which links 5-aminosalicy-late to itself through an azo bond. A small uncontrolled trial has suggested its efficacy in the enema form.²⁶ Another useful formulation is a watersoluble polymer that links 5-aminosalicylate by an azo bond to an inert polysulfanilamide. In an open protocal several patients with mild to moderate ulcerative colitis responded to this polymer. Similarly three other analogues of salazopyrin have been synthesised and suggested as potential therapeutic agents.²⁷
To counter the need for bacterial cleavage of the azo bond , specially in the treatment of Crohn’s ileitis, sustained release forms of 5-amino-salicylate have been developed. In an open trial, 92% of patients with Crohn’s ileitis and ileocolitis improved after 6 weeks of therapy with this agent.²⁶
All available experience suggests salazo­pyrin as the initia ltherapeutic choice in ulcerative colitis. Four gms/day is the maximum dose tolerated by most patients. Therapy should be continued as prophylaxis in patients who go into remission on a standard maintenance dose of 2 gins/day. Similarly salazopyrin is a reasonable initial choice in patients with acute Crohn’s disease. The drug does not appear to have a prophylactic role in patients with Crohn’s disease once remission has been achieved. In future, newer oral forms of 5-aminosalicylate should emerge as safe and clinically useful forms of therapy.
Though salazopyrin crosses the placenta, it has not been found to be harmful to the foetus²⁸ or to the new born being nursed by a mother taking the drug. Salazopyrin has also been used in other disorders such as radiation bowel disease, scleroderma, dermatitis herpetiformis and rheumatoid arthritis.^29,32
The mechanism of action of salazopyrin remains unclear. A possible antibacterial mode of action has been suggested because of its sulphonamide component. Possible effect of salazopyrin on systemic and local immunity have been studied. Inhibition of prostaglandin synthesis by salazopyrin has been suggested, however findings indicate that prostaglandins. may not be important mediators of inflammation in inflammatory bowel disease.³³ An alternative hypothesis suggests that salazopyrin or 5 aminosalicylate may work by increasing local levels of prostaglandins, which may act in a cytoprotective manner, Inhibition of potent chemotactic agents, which recruit inflammatory cells into sites of inflammation, may account for some of the anti-inflammatory effects of salazopyrin.³⁴
Salazopyrin has been shown to interact with folic acid and by competitive inhibition of folate conjugase cause folate malabsorption.³⁵ Metabolism of salazopyrin has been shown to be markedly reduced by the concurrent administration of cholestyramine, a nonabsorbable anion exchange resin.³⁶ A similar interaction has been reported between ferrous sulphate and salazopyrin.³⁷ Administration of broad-spectrum antibiotic concurrently, diminished salazopyrin metabolism probably due to a dimunition in gut flora,³
The commonest but least severe adverse reactions due to salazopyrin include nausea, vomiting, anorexia and headache. Heart burn epigastric distress and diarrhoea are seen dccasionally.^38,39
More serious reactions include various skin eruptions and a blue discolouration resembling cyanosis. Bloody diarrhoea with fever and rash has been reported. Reversible pancreatitis and a spectrum of hepatotoxicity has emerged. Pulmonary complication include one report of subacute fibrosing alveolitis, traçheo-laryngitis and eosinophillic pneumonia. Acceleration of heart rate has been confirmed and is postulated to be due to the salicylate moiety. Suppression of haemopoesis, megaloblastic and hemolytic anaemia have been described. Newly described, potentially important adverse effect is male infertiity, which is reversible.⁴⁰
Minor side-effects and mild allergic reactions can be overcome by dosage reduction or desensitization. As serious side effects are rare, salazopyrin remains a useful therapy for inflammatory bowel disease.

1. flu, K.M., Chowdhury, J.R., Zapp., B. and Fara, .LW. Small bowel absorption of sulfasalaziné and its hepatic metabolism in human being, cats and rats. Gastroenterology, 1979; 77 : 280.
2. Peppercorn, M.A. and Goldman, P. The role of intestinal bacteria in the metabolism of salicyla­ zosulfapyridine. J. Pharm. Exp. Ther., 1972; 181 555.
3. Peppercorn, M.A. and Goldman, P. Distribution studies of salicylazosulfapyridine and its meta­bolites. Gastroenterology, 1973; 64:240.
4. Svartz, N. The treatment of ulcerative colitis. Gastroenterologia, 1956; 86: 683.
5. Baron, J.H., Connell, P.M., Lennaro-Jones, J.E., and Jones, Sulphasalazine and salicylazosul­ phaadimidine in ulcerative colitis. Lancet, 1962; 1: 1094.
6. Dick, A.P., Grayson, M.J., Carpenter, R.G. and Petric, A. Controlled trial of sulphasalazine in the treatment of ulcerative colitis. Gut. 1964; 5 437.
7. Truelove, S.C., Watkinson, G. and Draper, G. Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. Br. Med. J., 1962; 2: 1708.
8. Truelove, S.C., Wffloughby, C.P., Lee, E.G., Kettlewell, M.G. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet, 1978; 2: 1086.
9. Misiewicz, J.J., Lennard-Jones, J.E., Connell, A.M., et al. Controlled trial of sulpha salazine in maintenance therapy for ulcerative colitis. Lancet, 1965; 1: 185.
10. Davies, P.S., and Rhodes, J. Maintenance of remission in ulcerative colitis with suiphasalazine or a high-fibre diet: a clinical trial. Br. Med. J., 197$; 1:1524.
11. Dronfield, M.W. and Langman, N.J.S. Comparative trial of sulphasalazine and oral sodium cromoglycate in the maintenance of remission in ulcerative colitis. Gut, 1978; 19 : 1136.
12. Willoughby, C.P., Heyworth, M.F., Pins, J. and Truelove, S.C. Comparison of disodium cr0-moglycate and sulphasalazine as maintenance therapy for ulcerative colitis. Lancet, 1979; 1 119.
13. Davies, P.S., Rhodes, J., Counsell, B. and Evans, B.K. Maintenance of remission in ulcerative colitis: effect of an orally absorbed mast cell stabilizer. Am. J. Gastroenterol., 1980; 74: 150.
14. Khan, A. A.K., Howes, D.T., Pins, J. and True-love, S.C. Optimum dose of sulphasalazine for maintenance treatment in ulcerative colitis. Gut, 1980; 21:232.
15. Goldstein, F. and Murdock, M.G. Clinical and radiologic improvement of regional enteritis and entercolitis after treatment with salicylazosulphapyridine. Am. J. Dig. Dis,, 1971; 16: 421.
16. Goldstein, F. and Thornton, J.J. Objective and subjective improvement with drug treatment in Crohn’s disease (Abstract). Gastroenterology, 1974; 66: 702.
17. Goldsten, F., Thornton, J.J. and Abramson, J. Anti-inflammatory drug treatment in Crohn’s disease. Am. J. Gastroenterol., 1976; 66: 251.
18. Anthonisen, P., Narany, F., Folkenoorg, 0. et al. The clinical effect of salazosuiphapyridine (Salazopyrin) in Crohn’s disease: a controlled double-bind study. Scand. J. Gastroenterol., 1974;9 :549.
19. Summers, R.W. Switz, D.M. Session, J.T. Jr. et at. National Cooperative Crohn’s disease study: results of drug treatment. Gastroenterology, 1979;77(4pt2) :847.
20. Singleton, J.W., Summers, R.W., Kern, F. Jr. et at. A trial of sulfasalazie as adjunctive therapy in Crohn’s disease. Gastroenterology, 1979; 79 (4 pt 2): 887.
21. Bergman, L. and Krause, U. Postoperative treatment with corticosteroids and salazosul pyridine (Salazopyrin) after radical resection for Crohn’s disease. Scand. J. Gastroenterol., 1976; 11: 651.
22. Khan, A. A.K., Pins, J., Truelove, S.C. An experiment to determine the active theraputic moiety of sulphasalazine. Lancet, 1977; 2 : 892.
23. Van Hees, P.A.M., Bakker, J.H., and Van Tongeren, J.H.M. Effect of suiphapynidine, 5-amino-salacylic acid, and placebo in patients with idiopathic procititis: a study to determine the active therapeutic moiety of sulphasalazine. Gut, 1980; 21 :632.
24. Campiert, M., Lanfranchi, G.A. Bazzoochi, G., Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet, 1981; 2270.
25. Ginsberg, A.L., Steinberg, W.M. and Nochomovitz, L.E. Evaluation of 4-aminosalicylate enemas in patients with left sided ulcerative colitis (Abstract). Gastroenterology, 1948; 86 1098.
26. Jewel, D.P., and Truelove, S.C. Disodium nodisalicylate in ulcerative colitis (Letter). Lancet., 1981;2 : 1168.
27. Chan, R.P.,.Pope, D.J., Gilbert , A.P., Sacra, P.J., Baron, J.H., Lennard, Jones, J.E Studies of two novel sulfasalazine analogs, ipsalazide and balsalazide. Dig. Dis. Sci., 1983; 28 : 609.
28. Mogadam, M., Dobbins, W.0. 3rd., Korelftz, B.T. and Ahmed. S.W. Pregnancy in inflammatory bowel disease: effect of suifasalazine and cortisteroids on fetal outcome. Gastroenterology, 1981;80 :72.
29. Goldstein, F., Khoury, J., Thornton, JJ. Treatment of chronic radiation enteritis and colitis with salicylazosulfapyridine and systemic cortisteroids. A pilot study. Am. J. GastroenteroL, 1976;65 : 201.
30. Dover, N. Salazopyrin (azulfidine) treatment in scleroderma. ft. J. Med. ScL, 1971; 7 : 1301.
31. Andreozzi, R.J. and Nuss, D.D. Dermatitis herpetiformis: treatment with azulfidine. Cutis, 1974; 13 : 366.
32. McConkey, B., Amos, R.S., Durhan, S., Forster, P. J: G., Hubball, S., Walsh, L. Sulphasalazine in rheumatoid arthritis. Br. Med. J., 1980; 280 442.
33. Rampton, D.S., and Sladen, G.E. Prostaglandin synthesis inhibitors in ulcerative colitis: flurbiprofen compared with conventional treatment. Prostaglandins., I981;21 : 417.
34. Sheer, J.S., Schwender, C.F. and Carethers, M.E. Inhibition of soybean lipoxygenase by sulfasalazine and 5-asninosalicylic acid:a possible mode of action in ulcerative colitis. Biochem. PharmacoL, 1983; 32: 170.
35. Reisenauer, A.M. and Haisted, C.H. Human jejuna.l brush border folate conjugase: characteristic and inhibition by salicyla.zosulfapyridine. Biochim. Biophys. Acta., 1981; 659 : 62.
36. Pieniaszek, H.J. Jr. and Bates, T.R. Cholestyramine-induced inhibition of salicylazosulfapyridine (Sulfasalazine) metabolism by rat intestinal microflora. J. Pharmacol. Exp. Ther., 1976; 198: 240.
37. Das, K.M. and Eastwood, M.A. Effect of hon and calcium on salicylazosulfapyridine metabolism. Scott Med. J., 1973; 18: 45.
38. Das, K.M., Eastwood, M.A., McManus, J.P. and Sircus, W. Adverse reactions during salicylazo sulpyridine therapy and the relation with drug metabolism and acetylator phenotype. N. Engi. J. Med., 1973;289: 491.
39. Singletion, J.W., Law, D.H., Kelley, L.M., Jr., Mehkjian, H.S., Sturdevant, R.A National Cooperative Crohn’s Disease study: adverse reactions to study drugs. Gastroenterology, 1979; 77 (4pt 2): 870-82.
40. Levi, A.J., Fisher, A.M., Hughes, K., Hendry, W.F. Male infertifity due to suiphasalazine. Lancet, 1979; 2 : 276.