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Lack of cross-reactivity between 5-aminosalicylic acid-based drugs: a case report and review of the literature.

BACKGROUND: 5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product. OBJECTIVE: To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third. METHODS: A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide. RESULTS: The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects. CONCLUSIONS: Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.

Adult↗

Effect of drugs on colonic eicosanoid accumulation in active ulcerative colitis.

The effect of immunosuppressive drugs, 4-aminosalicylic acid (4-ASA), acetyl 5-aminosalicylic acid (5-ASA), and ketotifen on human colonic eicosanoid accumulation was evaluated in view of enhanced accumulation in patients with active ulcerative colitis. Azathioprine (100 micrograms/ml), cyclosporin (100 micrograms/ml), and methotrexate (100 micrograms/ml) significantly inhibited, by 25-35%, prostaglandin E2 (PGE2) accumulation by organ-cultured colonic mucosa of ulcerative colitis patients. Methotrexate was the only immunosuppressive drug that inhibited leukotriene B4 (LTB4) accumulation (50%), whereas azathioprine inhibited the accumulation of leukotriene C4 (LTC4) (25%). 5-ASA and its metabolite, acetyl 5-ASA, inhibited by 20-70% PGE2, LTB4, and LTC4 accumulation in the culture, supporting the contention that acetyl 5-ASA is as active as 5-ASA in these respects. 4-ASA had no effect on any of the eicosanoids. Ketotifen, a mast cell stabilizer, significantly inhibited the accumulation of PGE2, LTB4, and LTC4 by 33-60%. These results suggest a potential, new, unrecognized mode by which the immunomodulators induce part of their therapeutic effects in inflammatory bowel disease and support the contention that acetyl 5-ASA is as active as 5-ASA. The results obtained also indicate that ketotifen, used effectively in the prevention of bronchial asthma, inhibits the accumulation of colonic eicosanoids and, thus, may be of value in the treatment of inflammatory bowel disease.

Adult↗

L-glutamine enemas attenuate mucosal injury in experimental colitis.

PURPOSE: The aim of this study was to investigate the role of 1-glutamine, short chain fatty acid, prednisolone, and mesalazine (5-aminosalicylic acid) enemas on mucosal damage and inflammation in experimental colitis. METHODS: Colitis was induced in rats with trinitrobenzene sulfonic acid in ethanol. Saline (n = 14), prednisolone (n = 13), 5-aminosalicylic acid (n = 14), 1-glutamine (n = 14), and short chain fatty acid (n = 13) enemas were applied twice daily to the rats for seven days after the induction of colitis. The sham group (n = 9) received only saline enemas. Rats were killed at the seventh day and their colonic macroscopic inflammatory scores were determined. Colonic mucosal gamma glutamyl transpeptidase activity and colonic mucosal malondialdehyde levels were measured. The same measurements but no enemas were done in the control group (n = 7). RESULTS: There were significant differences in macroscopic inflammatory scores between sham and colitis groups (P < 0.001). The macroscopic inflammatory scores of the colitis group were higher than the short chain fatty acid and glutamine groups (P < 0.05). Whereas the mucosal gamma glutamyl transpeptidase activity was diminished in prednisolone, 5-aminosalicylic acid, and short chain fatty acid groups when compared with the control group; in the colitis, sham, and glutamine groups the activity of this enzyme did not change. The mucosal malondialdehyde levels were significantly lower in the prednisolone and glutamine groups than in the colitis group. CONCLUSION: Only one of four agents tested, namely, 1-glutamine enemas, could decrease the severity of colitis both morphologically and biochemically. Moreover, L-glutamine prevented the colitis-induced oxidant injury in the colonic mucosa. On the other hand, prednisolone and short chain fatty acids seemed to improve only the physiologic changes of colitis.

Animals↗

Effects of sulfasalazine and a sulfasalazine analogue on the formation of lipoxygenase and cyclooxygenase products.

A sulfasalazine analogue, 5'-(2,4-dichlorobenzoyl)2'-hydroxyphenylacetic acid (CL 42A), potently inhibited the formation of 5-lipoxygenase products (leukotrienes B4 and C4 and 5-hydroxyeicosatetraenoic acid) by human leukocytes. Half-maximal inhibition of leukotriene production was obtained with 5 and 10 microM CL 42A after stimulation with serum-treated zymosan or ionophore A23187, respectively. CL 42A was equipotent to nordihydroguaiaretic acid and about 50 times more potent than sulfasalazine and benoxaprofen in studies on the inhibition of LTB4 formation in leukocyte suspensions stimulated with serum-treated zymosan. Furthermore, CL 42A had no inhibitory effect on the production of 15-hydroxyeicosatetraenoic acid after incubation of human leukocytes with ionophore A23187 in the presence of exogenous arachidonic acid. Sulfasalazine inhibited the synthesis of 5-lipoxygenase products (5-hydroxyeicosatetraenoic acid and leukotriene B4: IC50 250 microM, leukotriene C4: IC50 100 microM) in a concentration-dependent manner but had no effect on 15-hydroxyeicosatetraenoic acid formation. The metabolites of sulfasalazine, sulfapyridine and 5-aminosalicylic acid, and the isomer, 4-aminosalicylic acid, were all less potent than sulfasalazine as inhibitors of leukotriene formation. Both CL 42A (IC50 20 microM) and sulfasalazine (IC50 500 microM) inhibited the synthesis of thromboxane B2 and hydroxyheptadecatrienoic acid in human platelet suspensions after arachidonic acid stimulation. However, while CL 42A inhibited cyclooxygenase, the inhibitory effect of sulfasalazine was exerted mainly on thromboxane synthase. The platelet formation of 12-hydroxyeicosatetraenoic acid was not inhibited by CL 42A whereas sulfasalazine had a weak inhibitory effect.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.

Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.

Adult↗

Colonic targeting of aminosalicylates for the treatment of ulcerative colitis.

Aminosalicylates (5-aminosalicylic acid) represent drugs of first choice in the treatment of ulcerative colitis. Two different therapeutic approaches have been employed to target the active 5-aminosalicylic acid to its site of action. Either inactive azo-prodrugs (e.g. sulfasalazine, olsalazine, balsalazide) or special galenic formulations have been developed for topical delivery of 5-aminosalicylic acid to the colon. However, as intestinal physiology, the extent of ulcerative colitis as well as drug disposition demonstrate large interindividual differences, acute healing rates (40-80%) and the maintenance of remission are quite variable. Apparently, therapeutic effects depend on local concentrations of 5-aminosalicylic acid in the colonic mucosa whereas systemic drug exposure might be one determinant of side effects. In general, 5-aminosalicylic acid is well tolerated and withdrawal from therapy is rare. Following administration of azo-prodrugs (e.g. olsalazine), lower plasma concentrations and higher delivery into the colon of 5-aminosalicylic acid can be observed in comparison to special galenic formulations of 5-aminosalicylic acid. Whether such changes in drug disposition will affect therapeutic efficacy remains to be proved by clinical data. Consequently, selection of a particular agent should be based primarily on clinical efficacy, profile of adverse effects, patients' acceptance and economic considerations.

Administration, Oral↗

Bioavailability of 5-aminosalicyclic acid from slow release 5-aminosalicyclic acid drug and sulfasalazine in normal children.

The bioavailability of a controlled release 5-aminosalicyclic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration of N-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicyclic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.

Aminosalicylic Acids↗

Ethacrynic acid and sulphasalazine inhibit the generation of leukotriene C4 in rat stomachs: a possible gastric anti-ulcer mechanism in cold-restraint-stressed rats.

The role of gastric glandular mucosal leukotriene C4 in gastric ulceration, produced by restraint at 4 degrees C (stress) for 2 h in rats, was studied in relation to the ulcer-preventing effects of ethacrynic acid, sulphasalazine and its constituents (sulphapyridine and 5-aminosalicylic acid), AA-861 and ONO-1078. Stress itself significantly raised mucosal leukotriene C4 levels; pretreatment with ethacrynic acid, sulphasalazine, sulphapyridine or AA-861 antagonised these changes and reduced the severity of gastric ulceration. Mucosal mast cell degranulation was prevented by ethacrynic acid, sulphasalazine, 5-aminosalicylic acid, AA-861 or ONO-1078; the mucus-depleting effect of stress was also reversed by all these drugs, except for 5-aminosalicylic acid. The anti-ulcer effect of ethacrynic acid and sulphasalazine appears to be related to their influence on glandular mucosal leukotriene C4 levels.

Animals↗

Beclomethasone dipropionate (3 mg) enemas combined with oral 5-ASA (2.4 g) in the treatment of ulcerative colitis not responsive to oral 5-ASA alone.

BACKGROUND/AIMS: Beclomethasone dipropionate is one of the topical corticosteroids which appear to have minimal systemic effects. We evaluated whether combined therapy with Beclomethasone dipropionate enemas and oral 5-aminosalicylic acid could be effective in patients suffering from ulcerative colitis not responsive to oral 5-aminosalicylic acid as monotherapy. PATIENTS: In twenty patients, non responders to 5-aminosalicylic acid treatment (2.4-3.6 g/day) given for at least 6 weeks, Beclomethasone dipropionate enemas (3 mg/60 ml/day) were added for 4 weeks. METHODS: Efficacy of the combination was evaluated before and at the end of the treatment using a clinical, endoscopic and histological score. RESULTS: After a four-week treatment period, a significant clinical improvement in stool frequency (p < 0.01), stool consistency (p < 0.001), blood (p < 0.001) and mucus in stools (p < 0.05), was observed. Endoscopy and biopsy confirmed an improvement in the activity score at the end of the treatment (p < 0.001). Six patients (30%) achieved remission, ten patients showed an improvement (50%) and four (20%) showed no benefits. No adverse event was observed. CONCLUSIONS: Beclomethasone dipropionate enemas combined with oral 5-aminosalicylic acid may be a safe and useful therapeutic approach in the treatment of ulcerative colitis not responsive to oral 5-aminosalicylic acid alone.

Administration, Oral↗

Therapeutic efficacy of sulfasalazine and its metabolites in patients with ulcerative colitis and Crohn's disease.

We studied the therapeutic efficacy of sulfasalazine and its metabolites sulfapyridine and 5-aminosalicylic acid in nine patients with Crohn's disease and in 23 patients with ulcerative colitis. In a randomized, controlled trial, we treated 11 patients for six weeks with 1 g of sulfasalazine three times a day, seven patients with 0.5 g of sulfapyridine three times a day, and 14 patients with 0.5 g of 5-aminosalicylic acid suppositories three times a day. The clinical state of the disease was characterized by an activity index, quality of stool, and remission rate. In addition, we monitored plasma levels of sulfapyridine, 5-aminosalicylic acid, and their acetylated metabolites. The initial activity index (mean +/- S.D.) was significantly reduced by sulfasalazine (from 245 +/- 129 to 100 +/- 71; P < 0.001) and by 5-aminosalicylic acid (from 251 +/- 65 to 90 +/- 93; P < 0.0001), but sulfapyridine was without benefit. Stool quality was also improved by sulfasalazine (82 per cent of the cases) and by 5-aminosalicylic acid (79 per cent). The highest remission rate was achieved with 5-aminosalicylic acid (86 per cent), followed by sulfasalazine (64 per cent) and sulfapyridine (14 per cent). Our investigations show that 5-aminosalicylic acid is the active moiety of sulfasalazine and that this effective metabolite may be an alternative to sulfasalazine in inflammatory bowel disease.

Adult↗

Simplified oral pancreatic function test.

The standard Bentiromide test and a new modified test using p-aminosalicylic acid (PAS) as a pharmacokinetic marker for p-aminobenzoic acid (PABA) have been evaluated in the detection of pancreatic exocrine insufficiency in children. The conventional two day test using a colorimetric assay for urinary PABA discriminated poorly between five children with pancreatic insufficiency and 13 others with normal pancreatic function. Two further groups of patients, comprising 28 with pancreatic exocrine insufficiency and 20 with normal pancreatic function underwent the modified test, and urine samples were analysed by high performance liquid chromatography. The results showed a complete separation between groups. The use of PAS eliminates a number of sources of error inherent in a two day Bentiromide test and provides a simplified and accurate diagnostic test for pancreatic insufficiency. The PABA-PAS modified test enables collection of the urine to be done during a single six hour period.

4-Aminobenzoic Acid↗

5-aminosalicyclic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

Aminosalicylic Acids↗

Longterm olsalazine treatment: pharmacokinetics, tolerance and effects on local eicosanoid formation in ulcerative colitis and Crohn's colitis.

To examine pharmacokinetics and tolerance of long term administration of olsalazine (azodisalicylate), increasing doses of the drug were given for one year to 31 patients with ulcerative colitis (UC) and nine patients with Crohn's colitis (CC), refractory to, or intolerant of sulphasalazine, until sustained remission was obtained or a maximum of 4 g/day was reached. Colonic drug metabolism was studied by equilibrium in vivo dialysis of faeces. Complete azoreduction occurred in most cases. Concentrations of 5-aminosalicylic acid, but not N-acetyl-5-aminosalicylic acid, in faecal dialysates increased dose dependently. Serum concentrations disclosed no cumulation in the long term and olsalazine was well tolerated, although loose stools occurred transiently in some patients with extensive disease: this was associated with a larger proportion of unsplit olsalazine in the faecal dialysates. Patients with ulcerative colitis having a high prostaglandin E2 concentration (greater than ng/ml) determined by equilibrium dialysis of rectum, were less likely to benefit from treatment. Olsalazine is a very effective means of delivery of 5-aminosalicylic acid to the colonic mucosa in active disease. Use of the drug in controlled trials may be considered safe even in prolonged high dosage.

Adolescent↗

Review article: maintenance therapy in patients with ulcerative colitis.

British Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long-term therapy with a 5-aminosalicylic acid compound to maintain remission. Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5-aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5-aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under-dosing. The recent discovery that 5-aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator-activated receptor-gamma, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long-term therapy with 5-aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view. Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life-long doses of 5-aminosalicylic acid of > or =2 g/day for maintenance of remission in patients with ulcerative colitis.

Administration, Oral↗

Review article: induction therapy for patients with active ulcerative colitis.

5-aminosalicylic acid (mesalazine) is considered first-line therapy for active mild-moderate, left-sided or extensive ulcerative colitis. With modern delayed-release formulations, conventional doses are very well tolerated, and there is accumulating evidence that increasing the dose, to >4 g/day, leads to higher response rates and earlier symptom relief in patients with ulcerative colitis. There is evidence that combining oral and rectal (enema) formulations of 5-aminosalicylic acid leads to faster and higher remission rates. Despite the fact that clinical trials in ulcerative colitis have often used different endpoints, making it difficult to make objective comparisons, the evidence now strongly suggests that it is appropriate to start patients with mild or moderately active ulcerative colitis on doses of 5-aminosalicylic acid of at least 4 g/day. For those with extensive disease, adding rectal 5-aminosalicylic acid improves remission rates; the same seems likely to be true for limited disease, but robust evidence is lacking. Rectal 5-aminosalicylic acid may in fact be sufficient on its own for patients with active proctitis. Patients with mild-moderate ulcerative colitis who do not improve within 2 weeks of high-dose 5-aminosalicylic acid should have treatment augmented by oral steroids.

Administration, Oral↗

Intracolonic administration of zileuton, a selective 5-lipoxygenase inhibitor, accelerates healing in a rat model of chronic colitis.

BACKGROUND: 5-Lipoxygenase products play a part in inflammatory response. AIMS: The effect of intracolonic administration of zileuton (a 5-lipoxygenase inhibitor) on colonic damage and eicosanoid local release was assessed in a rat model of colitis. METHODS: Ninety rats with trinitrobenzenesulphonic acid induced colitis were randomised to receive placebo, 5-aminosalicylic acid (50 mg/kg), or zileuton (50 mg/kg) intracolonically for four weeks. Local eicosanoid release was monitored by intracolonic dialysis throughout the study. The colon was removed for macroscopic and histological assessment at weeks 1, 2, and 4 after colitis induction in 10 rats of each group. RESULTS: Zileuton significantly reduced macroscopic damage score after four weeks of treatment in comparison with the other two groups (p = 0.034). In addition, zileuton administration significantly increased the intracolonic release of both thromboxane B2 at week 1 (p = 0.05) and prostaglandin E2 at weeks 2 and 4 (p < 0.05). Zileuton and 5-aminosalicylic acid decreased leukotriene B4 release by 90% at day 3. CONCLUSIONS: Intracolonic zileuton, compared with 5-aminosalicylic acid and placebo, seems to improve the course of the disease in a model of chronic colitis. This effect may be related to an increased and maintained production of prostaglandin E2 together with inhibition of leukotriene B4 synthesis.

Aminosalicylic Acids↗

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.

The 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 less than 0.001). In all healthy volunteers PGE2 concentrations decreased slightly (p less than 0.05) 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 less than 0.05) which returned to pretrial values (p less than 0.05) 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.

Adult↗

The short- and long-term safety of 5-aminosalicylate products in the treatment of ulcerative colitis.

5-aminosalicylic acid agents are effective in the treatment of ulcerative colitis. Balsalazide, mesalamine, and olsalazine are alternative formulations to sulfasalazine for the delivery of 5-aminosalicylic acid. The newer compounds might be better tolerated than sulfasalazine in some patients, as long as the intolerance is not due to hypersensitivity to 5-aminosalicylic acid. Adverse events requiring the withdrawal of therapy seem to occur less frequently with balsalazide, mesalamine, and olsalazine compared with sulfasalazine. If patients are unable to tolerate any one of these three 5-aminosalicylic acid-releasing preparations, they might be able to tolerate one of the others, as long as the intolerance is not due to hypersensitivity to 5-aminosalicylic acid.

Adolescent↗