Safety profile of the new 5-- ASA based compounds

5-aminosalicylic acid (5-ASA) preparations were anticipated to 
be and generally are better tolerated than sulphasalazine. Minor side effects such 
as headache, dizziness, abdominal pain and nausea do occur but are not more 
frequent than in placebo-treated patients. Approximately 10% of patients 
thought to be allergic to sulphasalazine are also allergic to 5-ASA. An 
idiosyncratic reaction with worsening of symptoms can occur. Diarrhea is more 
common with olsalazine, and it is due to the effect of olsalazine itself on the small 
bowel. not the 5-ASA component. There are case reports of pancreatitis, 
pericarditis and bronchospasm, retrosternal chest pain, mild neutropenia, 
nephrotic syndrome and hair loss associated with 5-ASA treatment. Patients 
with oligospermia due to sulphasalazine have improved when switched to 5-ASA. 5-ASA enemas can cause local irritation or other effects resulting from 
enema tip insertion.

In 1977 1t was Jemomtratcd that 5-ASA 1s the active moiety of sulphasalazine for the treatment of ulcerative coltt1s (13 ).This has since been confirmed ( 14), and led to the development of two types of agents: compounds in which sulfapyndine is replaced by another carrier molecule, considered to be less likely to produce side effects.(One ingenious structure is obalazine, where two molecules of 5-ASA are Joined by an azobond.These compounds require bacterial enzyme action to be split into the active compounds in the distal ileum and colon); and 5-ASA (mcsalaminc) with various coaring systems to retard upper gastroinrcst1nal absorption and thus minimize possible renal tox1c1Ly.
It appears reasonable to assume that the spectrum of untoward effects 1s similar for the various rnesalaminc products and that the s1Je effects caused by a new azo-compound of 5-ASA coulJ differ in certain respects from mesalamine formations.

MESALAMINE
&cause sulphasalazine was already in din1ql use with mo:.t of the side effects thL1ught to be related to the suliapyndine m01ety, 5-ASA, the active moiety, was anttc1pated to be ~afer to use and m mtroductton tl> clinical med1c111e followed a wmewhat different sequenc.:e.Initial animal experimenb usmg 5-ASA by Calder er al (15) on rats showed nephrntox1c1ty.Smgle mtravenous mjection of 5-ASA al dosages of 1.4, 2.8 and 5.7 mM/kgcaused renal comcal necrosis in 2 3 of 60 rats, 13 of which also had associated papillary nec.:rosis.l ligher dosages tended to produce more severe les1om, but there were exceptions.As 5-ASA has molecular sunilanttes to phenacetin, rhe sporadte and mcomplere 111c1dencc of renal lesions was thought to be due to a sumlar mechanism seen with anal-gcsKs.
An open srudy of 5-ASA (Pentasa; Nordic Lahomtories) was perfonncd by Ra:,mussen et al ( 16) m 18 patients with Crohn's d1~e,1.,eunresponsive ni other dn1 gs.Oral Pemasa, 500 mg tid, was effective and was not associated with any side effects.In pamcular, there was no change in the urinary sediment or 51 Cr EDT A plasma clearance.None of the other biochemical and hematological tests showed any alteration.
Since then there has been only one report of a patient who developed nephrottc syndrome after five months of treatment with mesalamine 800 mg tid ( 17).In the study by Riley et al ( 18) two of 21 patients treated with Asacol (Norwich-Eaton) 1200 mg twice daily for four weeks developed up co a twofold rise m plasma creatinme which returned to normal after discontinuamm of treatment.One further patient has been reported to have a decrease in creatinine clearance on Asacol treatment ( 19).This patient had previously been treated with sulphasalazine without J1fficulry.In the post marketing adverse reaction reporting of various Salofalk (lnterfalk) preparations between 1984 and 1989, using 663,608 patients/treatment cycle, only six cases of interstitial nephritis were noted (personal commumcation).
Mesalamine was initially used in patients allergic or intolerant to sulphasalazine {19-26).Approximately 85% of these patients were able to tolerate mesalamme.It appears that patients who experienced allergic and upper gastrointestinal effects while receiving sulphasalazine commonly experience a similar reaction to mesalamine (20,21,23,25 ).Leukopenia has been reported on substitution of mesalamine for sulphasalazme in a patient who haJ developed leukopenia while being treated with sulphasalazine (25).In a randomized trial rhe incidence of headache was reported to occur with sumlar frequency during treatment with mesalamine or sulphasalazine (27).Riley et al (28) noted that headache resolved during continued therapy more often in patients treated with mesalamine (80%) than in those receiving sulphasalazine (50%) and that regular headaches were more common with sulphasalazme (P<0.02).Donald et al ( 22) noted that two patients who were re1..e1ving Asacol 1600 mg/day and expem:nung headaches were free from headaches at a redu1..ed dlhe of 800 mg/day.Th 1s sug-gests that nor all of the allergic side effects or intolerance to sulphasalazme are related to the sulfapyridine component.In a recent mtemattonal randomized double-blind study comparing sulphasalazine and mesalamine the incidence of headache and ep1gastric pain was similar in the two groups, and the incidence of hypersensitivity reacuons and nausea and vom1tmg was four times more in the su lphasalazme group compared to the mesalamine group (29).
In the National Cooperative Crohn's Disease Study (36), apart from the occurrence of loose stools or oven d iarrhea, the reported adverse events were not more common m the sulphasalazme group than m the placeho group.
The cause of olsalazme-induced diarrhea 1s not known.Studies m patients with permanent ileostorn1cs have shown that olsalazine dose-dependently mcreases tleosromy output (37).This is not mediated by pro~ta• glandin E2 or F2.Experimems in rats have shown that olsalazme can mh1bn small intestinal transport systems anJ that, at high concentratiom, it can induce chloride anJ water secretton (38,39).In a clinical study, diarrhea during olsalazine therapy occurred more often m patients with pancol1m than in those with distal ulcerattve colitis (40).

CONCLUSIONS
The new 5-ASA agents are generally well wlerateJ.Overall 80 to 90% of panents intolerant to sulphasalazmc can tolerate the new 5-ASAs.Ten to 20% have a similar allergic reaction Lo the new agents as LO sulphasala,me.Diarrhea due to olsalazine 1s dose-related anJ may be due to its effect on rhe small intestine.The new agents are capable of Jclivering the active agent pynJmc, 5-ammosalicylic auJ, anJ to the small bowel m Crohn's Jisease, placcb.)m patients w,ch 1<llllpath1L but there is a possibility Lhat absorption proctitis: A study to determine the active chcrnpcurac moiety of sulph,1may leaJ to nephrotox1cily with higher sahmne.Gue 1980;2 I :632-5.doses given over prolongcJ periods.