Clinical experience with 5-aminosalicylate preparations in inflammatory bowel disease A review

The e fficacy of 5-ASA tablets is around 65 co 70% in patients with active ulcerative colitis, whereas the efficacy of the rectal preparations approach 100% when the treatment is for active dis cal disease. When there is more extensive left sided colonic disease, the efficacy cif 5-ASA rectal preparations is not as high, but it is still much improved over that seen with oral 5-ASA preparations. There is no data available for total colonic disease of either ulcerative colitis o r Crohn's disease. There is no controlled maintenance data availab le for Crohn's d isease using 5-ASA preparations and no controlled or comparison data available for rectal preparations in Crohn's disease. There are no controlled dosc-re~ponse studies of 5-ASA in patients with Crohn's disease. Thus, the most "therapeutic" dose is not known. The author's anecdotal evidence reports char patients with Crohn's disease affecting the rectum or left colon respond poorly to 5-ASA enemas. However. with continued use of more than six weeks a t least a 50 to 60~;, respon e is seen. In contrast, virtually a ll patients with ulcerative proctitis respond by six weeks and all are controlled by IO to 12 weeks. When oral 5-ASA is compared with conventional oral sulfasa lazine therapy, the efficacy is comparable. However, with 5-ASA the incidence of side effects is considerably lower; the number of patients d iscontinuing therapy is less; patient compliance is better, especially for che long term; dosage increase following inadequate action is more readily possible; and bacterial activation of the drug given is not nl!cessary Can J Gastrocntcrol 1987; l ( I ):28-32 Key W o rds: 5-Aminosalicylic acid ('5-ASAJ, Crohn's disease, Oral (tablets). Rectal (enemas. su/Jpmitories). Ulcerative co/iris, Ulcerati1•e Jn·octitis Corrcs/)ondc11cc and rcpnnl1 Or C.N Williams. D11•1s1on of Gamocnrerology, Deparrmenr oj Mcdicmc. Dallwwie Unri•ernry. Halifax, Ncwa Scor,a 83H J 1\/ 2 Rece1t>ed for /ncbl1cc.11wn February. 1987 Acceprcd A/Jril /''i, /ll87 28 SUI FASALAZINE lSALAZOPYRINE PHARmacia) (I) is an azo compo und compromised of two moieties; sulfapyridinc and 5-aminosalicyl ic acid ( 5-ASA) Sulfapyridine acts as the vehicle and ny ib binding with 5-ASA prevcnrs absorr· tion of 5-ASA in the small in testine The active part is 5-ASA, released by bacte· rial cleavage in the colon ( 2). Sulfapyridinc is associated with most of the side effects associated with sulfasalazine (),4) As of September 1986, there arc two preparations in Canada of 5-ASA available on the market: Asacol (Norwich Eaton) 400 mg cable ts, and Salofalk (imer· folk) 4 g enemas. Other preparations available for investigative and compas· sionate use include Salofalk. 2 50 mg tab· le ts; Rowasa (Reid-Rowell, USA), 250 mg tablets; Penrasa (Fcrring, Sweden), 250 mg tablets.ind Oipcncum (Pharma· cia), 2 50 mg tablets. Sn lofalk suppositories arc available in 2 50 and 500 mg size and Rowasa supposimries in 500 mg. Rowasa is also available as a 4 g cncm;,. CAN J GASTROFNI I Rlll Slow release oral prepararions include: Asacol, Salofalk, Rowasa and Penrnsa. Asacol is coated with Eud ragit-S, which enables the pill to be released above pH 7 in the colon , dissolution being slow at pH 2 to 6 and 4 to 8 h at a pH of7 .5. Salofalk, which is coated with ethylcellulose plus Eudragit-L. is released at pH greater than 5.6 in the ileum anJ is dissolved in I. 5 to 2 h ar pH 7. 5. Rowasa issimilarto Salofalk, while Pcntasa has an ethyl-cellu lose covering only and is s::iiJ to be available at any pH. It should, therefore, be of particuh1r use for treatment of Crohn's diseasc in the stomach and small intestine. The 5-A SA oral preparations, which require colonic bacterial action for release of the active mo iety, include Salazopyrine, which is 5-ASA and sulfopyridine; Oipentum, which is a dimer of two molecules of 5-ASA: and Po lyasa, which is a dimer of 5-ASA and sulfanilamidc ethylene polymer. SIDE EFFECTS The side effects of o ral p reparatio ns of 5-ASA arc infrequen t and dose related, with headache, n::iusca. epigasrric distress and diarrhea being the most common complaints. However, with salazopyrinc, side effects arc mo re frequent, up to 30% ( 5), are mainly dose re lated with occasio nal hype rsensitivity reactions ll .4). The side effects include anorexia, nausea, vomi ting, ep igastr ic distress, rash and rare reactions such as agranulocytosis, aplastic o r he molytic anemia, pancreatitis. d rug-induced bloody diarrhea (6) and infertility (7,8) being ascribed to hypersensitivity reactions. Side effects of the rectal fo rms include occasiona l recta l soreness and possible hair loss and the initial inability to retain the 5-ASA supposi to ries anJ enemas. There arc no readily available commercial preparatio ns of sulfasalazine for rectal use at the present time. Con traindications to 5-ASA therapy include: severe renal disease; severe liver disease; active peptic ulcer; ;ind coagulopathies. Hypersensitivity re;ictions h;ive been rarely described such as, drug rnsh . fever, bronchospasm and a lupus-like syndro me. Drug interactions arc theoretica ll y possible wit h su lphanylurcas. coumarins. methotrexacc. probenicid. Vol. I No I Octoher 1987 ---~ ~ ~ ~ --r=,.,.w----. w--.wspironolactonc. furosa mide and rifampin (manufacturer's safety suggestions). 5-ASA USE 5-ASA 1s useful in inflammatory bowel disease. both ulcerative coli tis and Croh n's disease. Its use has been tested in the treatmen t o f acute flare-ups of ulcerative col itis as well as in maintenance therapy, and for active C ro hn's


CAN J GASTROFNI I Rlll
Slow release oral prepararions include: Asacol, Salofalk, Rowasa and Penrnsa.Asacol is coated with Eud ragit-S, which enables the pill to be released above pH 7 in the colon , dissolution being slow at pH 2 to 6 and 4 to 8 h at a pH of7 .5.Salofalk, which is coated with ethylcellulose plus Eudragit-L. is released at pH greater than 5.6 in the ileu m anJ is dissolved in I. 5 to 2 h ar pH 7. 5. Rowasa issimilarto Salofalk, while Pcntasa has an ethyl-cellu lose covering only and is s::iiJ to be available at any pH.It should, therefore, be of particuh1r use for treatment of Crohn's diseasc in the stomach and small intestine.
The 5-A SA oral preparations, which require colonic bacterial action for release of the active mo iety, include Salazopyrine, wh ich is 5-ASA and sulfopyridine; Oipentum, which is a dimer of two molecules of 5-ASA: and Po lyasa, which is a dimer of 5-ASA and sulfanilamidc ethylene polymer.

SIDE EFFECTS
The side effects of o ral p reparatio ns of 5-ASA arc infreque n t and dose related, with headache, n::iusca.epigasrric distress and diarrhea being the most common complaints.H owever, with salazopyrinc, side effects a rc mo re frequent, up to 30% ( 5), a re mainly dose re lated with occasio n al hyp e rsensitivity reaction s ll.4).The side effects include a norexia, nausea, vo mi tin g, ep iga str ic distress, rash and rare reactions such as agranulocytosis, aplastic o r he m olytic a nemia, pancreatitis.d rug-induced bloody diarrhea (6) and infertility (7,8) being ascribed to hypersensitivity reactions.
Side effects of the rectal fo rms include occasiona l recta l sore ness and possible hair loss a nd the initial inability to retain the 5-ASA supposi to ries anJ enem as.There arc no readily available commercial preparatio ns of sulfasalazine for rectal use at the present time.

5-ASA USE
5-ASA 1s useful in inflammatory bowel disease.both ulcerative coli tis and Croh n's disease.Its use has been tested in the treatmen t o f acute flare-ups of ulcerative col itis as well as in maintenance therapy, and for acti ve C ro h n's disease.

ORAL PREPARATIONS
Ulcerative colitis: In a two-week clinica l trial (9).l 3 of 20 patients given 2 g/ day Oipentum for active ulcerative coli tis improved, compared to e igh t of 20 p;itients given ;i placebo.O ne patient given Oipe ntum worsened compared to nine p;iticnts in the placebo group.
In an open trial of Polyasa ( 1.6 g/ J ,1y for six weeks) seven of LO patien ts cli nically improved ( l l l.No con trol data was available for treatmen t of u lccra ti vc colitis with Polyasa. Oral 5-ASA (Asacol 1.2 g/d ay) was compared with Sa lazopyrine (2 to 3 g/d ay) in th e maintenance treatment of ulcerative colitis in 6 7 patients ( 12 ).Relapse at four months occu rred in nine of 34 (26%) taki ng Asacol a nd six of 33 ( 18%) raking sa lazopyrin e (no significa n t difference).In a later report ( 12), seven of 32 patients ( 22°i.) re lapsed a t six months on Asacol, 2. 7 g/day, compared to five of 2 5 (20<\) taking salazopyrine, 2 to 3 g/day.ln another open trial ( 13 ), the effect of Asacol ;ilone. 2 g/dny. in patients with u lcerative colitis was compared with a Crohn's disease: Penrnsa has been used nt ;i dose of I .5 g/dny for IO days in 12 patients with active Crohn's dise;ise ( 14).There was no ch ange in the Croh n's dise;isc activi ty index (COAi ) versus pl ace bo.In another study using Pc nrnsa ;i t I .5 g/day or six weeks in 18 pmicnts, rhe cl inical co nditio n of I 3 patie nts improved whi le three worsened.The COAi before treatmen t was 226 ( normal.less than 150) and fe ll to 99 after treatment ( 15).In a double-blind study of oral 5-ASA (Salofalk.I .5 g/day ) vcrsussulfasalazinc ( 3 g/day).13 of 15 patie nts taking 5-ASA and 12 of 15 patients caking sulfasalazine improved afte r eight weeks ( 10).In the group taking Salofalk .the C OAi before treatment was 308 .i. 72 falling to 11 9 +:-82, (P < 0.0001 ).In rhe group taking su lfasalazinc rhe C OAi before treatment was 310.L 75.dropping to 162 + 11 5 (P<0.000I ) afte r trea tm ent.

Disease Activity
Ther~• wa, an apparent se, difference in rl'spon,e .ill the males in thl' active group had heall'd rnmplett'h m , 1x \\'eeks, whereas thrct• tif the six wonwn had improved s1gnif11.antlyhut were nut com• pktl'lv hl•aled In .1 concurrl'nt study 117 l.In a separate study of patients with soli tary ulcers of the rectum, symptoms disappeared completely when 5-ASA suppositories were given ( LS) The ulcers d isappeared on sigmo1doscopy and biopsies confirmed this rapid resolution of pathology ( Figures 2A and B).'1 .9I 3.4 -----~ ulcerative colit b. were highly effective There \\ as no difference between the number of patien ts, the sex rntin, the age.the \\'l'1ght and the dur:rnon of the disease in the active ;i nd placeho grour or m the percenwge of patients wuh thl' firs t episode.the baseline disease activ• icy sccm• in the males or females, or tht• use of concu rrent medication.However there were six "dropouts" m the 5-ASA group and 22 in thl' placebo group Thi~ was related t0 offering active medication to those who were not responding at three weeks.The physician rnu ng of "much irn proved" showed a significant difference for males who responded better than females w hen ench was compared to placebo.Twt•nty-two of 17 males responded posnivcly m 5-ASA encm;is compared to eight of 17 receiving pl::icebo (P 0 000 I).The female resronsc was 26 of Wand 14 of 40, respectively (P c. 0 06) This sex difference was, in p::irt, relritcd to the higher DAI for males before treat mrnt, 8.43 versu s () 46.The DAI of females was lower before treatment corn pared to the placebo female group 6.46 verus765(P< 003) In an Italian mulucentre study (22), usmg 4 g 5-ASA or I 00 mg hydrocornsone enemas for 15 days in patients with left sided ulceranve cnlms, there was clin- In a controlled trial of patients with ulcerative colitis.olsalazine (Dipcncum) was found to be no more effective than placebo when used rectally (23) In conclusion, oral 5 ----------~-~-~-~--r=,.,.w----.w--.wspironolactonc.furosa mide and rifampin (manufac ture r's safety suggestions).

Figure
IA shows representative histological changes of acute proctitis with crypt abscesses.In contrast, Figure I B shows norm::il appearance of the rectum ,t•en atrer s1\ weeks uf treatment with 5-ASA suppositcmcs.The suppositories were safe, well tolerated.covered the ::irea 111flamed and were very effective.

TABLE 1 5
-ASA ,n inflammatory bowel disease second group of patien ts who were more sick and requ ired As;icol plus pred niso ne. 10 to 15 mg/day.There were 19 patients in the first group and 12 patients in the seco nd .Relapse occurred in two of 19 ( 10%) with Asacol, and in five of 12 ( 41 '\) wi th the d rug combina tion.
Index: A qualitative rating derived by summing four categories

TABLE 2
Effect of 5-ASA on the Disease Activity Index of patients with distal proctitis • 5(JJ mg suppos1tones three times o day n 6 h period to measure the ex tent of retrograde passage of the suppository In patients with active, disrn l proctitis the rectum and sigmmd colon was covered adequately for 3 h after one supprn,nory. of choice for distal ulcerative colttis and are effective when convenlional therapy foils.When there is a slow or no effect, "think" rectal Crohn's disease.Rectal preparatio ns of 5-ASA arc useful tn patients with "solitary" rectal ulcers aticm of 5-ASA suppositories m the treatment of patients with acuvc distal procmis: measurement of extent of spread usmg 99m Tc-5-ASA supposlt• ones.Dig Dis Sci 1987 (In press) 18. Williams CN, Malatjalian D The use of 5-ASA in patients with solitary rectal ulcers.lntcrfolk Canada Monograph, September 1987 19 Maier K Long-term prophylactic ust' of 5-ASA suppositories m coitus ulccrosa Verd Kranathcutcn 1983;1 :62-5 20.Sidorov JJ, Williams CN.Open study ot 5-ASA suppositories tn ulcerauvc pmctitis and ulccrauvc colitis.Clin Invest Med 1986:9A60.2 t Smhcrland LR, Marnn F. Treatment of pauents with left-sided colitis :ind distal proctit1s with 5-ASA enemas, a plnccbo•controlled.prospccuvc, randomized study.Dig Dis Sci, 1987 (In press) 22. Camp1cn M. Lanfranchi GA.Bosch1 S.