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.     

Comparative analysis of the in vitro prosecretory effects of balsalazide, sulfasalazine, olsalazine, and mesalamine in rabbit distal ileum

BACKGROUND: The aminosalicylates remain foundation therapy for mild-to-moderate ulcerative colitis. Pro-drug 5-aminosalicylic acid (5-ASA; mesalamine) formulations have been developed to prevent 5-ASA from the proximal absorption and release of mesalamine, to decrease inflammation, and to improve colonic absorption. Clinically, pro-drugs such as olsalazine have been associated with dose-dependent diarrhea, which was likely secondary to ileal secretion induced by the azo linkages, in 17% of patients. The present study tested the hypothesis that the use of all compounds with azo linkages leads to increased secretion. METHODS: Intestinal tissue was randomly assigned to serve as controls or to receive brush border addition of equimolar concentrations of the compounds, and the change in short-circuit current was measured. RESULTS: Mesalamine did not induce secretion at any dose. Mean equivalent doses (0.1 to 10 mM) of balsalazide (range, 6.3 +/- 1.5 to 16.7 +/- 1.3 microA/cm2), olsalazine (range, 2.0 +/- 1.0 to 7.0 +/- 2.1 microA/cm2), and sulfasalazine (3.2 +/- 1.1 to 6.2 +/- 1.5 microA/cm2) significantly stimulated (P < 0.001) secretion. The values for the effective dose that is half the maximal dose for secretion induced by sulfasalazine, olsalazine, and balsalazide were 0.4, 0.7, and 0.9 mM, respectively. CONCLUSIONS: This study is the first to demonstrate that the use of pro-drugs with azo bonds leads to increased ileal secretion at equimolar concentrations of 5-ASA. Physicians should use caution when providing higher doses of the pro-drug forms of 5-ASA to their patients, as this could lead to increased diarrhea.     

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.     

The efficacy of oral 5-ASAs in the treatment of active ulcerative colitis: a systematic review

The authors set out to critically review the current data on the efficacy of oral 5-aminosalicylic acid (5-ASA) agents for active ulcerative colitis (UC). Thirty-one studies were identified; 19 met entry criteria. Three trials with mesalamine showed statistical significance versus placebo; those with olsalazine or balsalazide did not. No agent was statistically different from sulfasalazine. In 2 of 3 trials of balsalazide versus mesalamine, results for defined primary and secondary endpoints failed to demonstrate statistically significant differences. Studies suggest that mesalamine is superior to placebo for treating active UC. Five-ASA products appear to be as effective as sulfasalazine, but available data do not suggest a difference in efficacy between any of the 5-ASA preparations.     

Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine.

Prostaglandin E2 (PGE2) level in rectal mucosa excised from 17 patients suffering from ulcerative colitis was 2-fold higher than that found in rectal mucosa of 17 normal subjects: 2.0 +/- 0.4 and 0.9 +/- 0.2 ng per mg of wet tissue, respectively. Accumulation of PGE 2 in 24-hr cultures of rectal mucosa specimens obtained from patients with ulcerative colitis was 112% higher than that observed in cultures from control subjects. Addition of sulfasalazine, sulfapyridine, and 5-aminosalicylic, acid to the culture medium of ulcerative colitis mucosa resulted in inhibition of PGE2 production by 34, 32, and 62%, respectively, compared to rectal specimens cultured in drug-free medium. These results suggest that PGE may mediate the inflammatory response in ulcerative colitis and that some of the therapeutic effect of sulfasalazine and its constituents are related to the inhibition of PGE synthesis.     

Studies of two novel sulfasalazine analogs,ipsalazide and balsalazide

Sulfasalazine appears to exert its beneficial effect in colitis by releasing 5-aminosalicylic acid in the colon, but its use can be limited by side effects. Ipsalazide and balsalazide are novel sulfasalazine analogs designed to release 5-aminosalicylic acid and a nontoxic carrier molecule in the gastrointestinal tract. They have a low oral toxicity following single or repeat administration to mouse, rat, and ferret, and balsalazide is not mutagenic in the Ames test. Ipsalazide and balsalazide are split in rat and man, and the urinary and fecal excretion pattern of the 5-aminosalicylic acid released is similar to that of sulfasalazine; the carrier molecules are absorbed to a lesser extent than the sulfapyridine derived from sulfasalazine. These two analogs deserve therapeutic trial.     

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs

Measurements of luminal pH in the normal gastrointestinal tract have shown a progressive increase in pH from the duodenum to the terminal ileum, a decrease in the caecum, and then a slow rise along the colon to the rectum. Some data in patients with ulcerative colitis suggest a substantial reduction below normal values in the right colon, while limited results in Crohn's disease have been contradictory. Determinants of luminal pH in the colon include mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates and mucosal absorption of short chain fatty acids, and possibly intestinal transit. Alterations in these factors, as a result of mucosal disease and changes in diet, are likely to explain abnormal pH measurements in inflammatory bowel disease (IBD). It is conceivable that reduced intracolonic pH in active ulcerative colitis impairs bioavailability of 5-aminosalicylic acid from pH dependent release formulations (Asacol, Salofalk) and those requiring cleavage by bacterial azo reductase (sulphasalazine, olsalazine, balsalazide), but further pharmacokinetic studies are needed to confirm this possibility. Reports that balsalazide and olsalazine may be more efficacious in active and quiescent ulcerative colitis, respectively, than Asacol suggest that low pH may be a more critical factor in patients taking directly pH dependent release than azo bonded preparations. Reduced intracolonic pH also needs to be considered in the development of pH dependent colonic release formulations of budesonide and azathioprine for use in ulcerative and Crohn's colitis. This paper reviews methods for measuring gut pH, its changes in IBD, and how these may influence current and future therapies.     

Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention

Sulfasalazine, olsalazine, balsalazide, delayed-release mesalamine, controlled-release mesalamine, mesalamine pellets, and Multi-Matrix System mesalamine are effective first-line therapies for the treatment of mildly to moderately active ulcerative colitis and for subsequent maintenance of remission. For induction therapy it is unclear if there is a dose response above 1.5 g, and for maintenance therapy existing data do not support a dose response above 1.5 g. Sulfasalazine has more frequent side effects than olsalazine, balsalazide, and mesalamine formulations. Once-daily dosing with multi-matrix system mesalamine 1.2 g tablets may lead to optimal compliance. Mesalamine >/= 1.2 g and sulfasalazine >/= 2 g reduce the risk of colorectal cancer in patients with ulcerative colitis. Drug formulations, efficacy expectations and dose response, toxicity expectations, compliance considerations, and chemoprevention considerations are reviewed.     

Colon-specific prodrugs of 4-aminosalicylic acid for inflammatory bowel disease

Despite the advent of biological products,such as antitumor necrosis factor-αmonoclonal antibodies(infliximab and adalimumab),for treatment of moderate to severe cases of inflammatory bowel disease(IBD),most patients depend upon aminosalicylates as the conventional treatment option.In recent years,the increased knowledge of complex pathophysiological processes underlying IBD has resulted in development of a number of newer pharmaceutical agents like low-molecular-weight heparin,omega-3 fatty acids,probiotics and innovative formulations such as high-dose,oncedaily multi-matrix mesalamine,which are designed to minimize the inflammatory process through inhibition of different targets.Optimization of delivery of existing drugs to the colon using the prodrug approach is another attractive alternative that has been utilized and commercialized for 5-aminosalicylic acid(ASA)in the form of sulfasalazine,balsalazide,olsalazine and ipsalazine,but rarely for its positional isomer 4-ASA-a wellestablished antitubercular drug that is twice as potent as 5-ASA against IBD,and more specifically,ulcerativecolitis.The present review focuses on the complete profile of 4-ASA and its advantages over 5-ASA and colon-targeting prodrugs reported so far for the management of IBD.The review also emphasizes the need for reappraisal of this promising but unexplored entity as a potential treatment option for IBD.     

Olsalazine as an alternative therapy in a patient with sulfasalazine-induced eosinophilic pneumonia

A man with Crohn's colitis developed eosinophilic pneumonia after treatment with sulfasalazine. Challenge with sulfapyridine revealed that this component of sulfasalazine was the likely causative agent. Treatment with olsalazine, a 5-aminosalicylic acid compound (disodium-azodisalicylate), was well tolerated without recurrence of pulmonary symptoms.     

Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis

OBJECTIVE: Balsalazide is a novel azo-bonded 5-aminosalicylic acid treatment for mild-to-moderate ulcerative colitis. The study objective was to compare symptomatic remission rates with balsalazide and mesalamine while controlling for extent of disease and time since diagnosis in patients with active, mild-to-moderate ulcerative colitis. METHODS: A total of 173 patients with sigmoidoscopically verified ulcerative colitis were randomized to 8 wk of double-blind treatment with balsalazide 6.75 g/day or mesalamine 2.4 g/day. Both treatments provided 2.4 g/day of oral 5-aminosalicylic acid. Patients maintained symptom diaries throughout the treatment period. RESULTS: Overall, 46% of balsalazide- and 44% of mesalamine-treated patients achieved symptomatic remission. Higher response rates were noted in newly diagnosed patients with < or = 40 cm of disease (68% vs 61%) than in recently relapsed patients with >40 cm of disease (36% vs 25%). The median time to symptomatic remission was 12 days shorter with balsalazide (25 days) than with mesalamine (37 days). Significantly more balsalazide patients showed sigmoidoscopic (p = 0.002), stool frequency (p = 0.006), rectal bleeding (p = 0.006), and physician's global assessment score (p = 0.013) improvement by 14 days than did mesalamine patients. Similar proportions of patients reported adverse events (54% vs 64%), which were most commonly related to the gastrointestinal and central and peripheral nervous systems. CONCLUSIONS: Balsalazide is an effective and safe treatment for mild-to-moderate ulcerative colitis. Improvement of symptoms occurs considerably earlier with balsalazide than with mesalamine.     

Adverse effects with oral 5-aminosalicyclic acid

Two patients with ulcerative colitis and a past history of allergic reactions to sulfasalazine had similar reactions when treated with 5-aminosalicylic acid. This suggests that, at least in some patients, the adverse effects of sulfasalazine are due to 5-aminosalicylic acid rather than sulfapyridine. Desensitization to sulfasalazine was successfully carried out in one patient but was not attempted in a second.     

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.     

Relapse-Preventing Effect and Safety of Sulfasalazine and Olsalazine in Patients with Ulcerative Colitis in Remission: A Prospective, Double-blind, Randomized Multicenter Study

Forty-nine patients with ulcerative colitis in remission were entered into a prospective, double-blind, multicenter trial comparing the relapse-preventing effect and safety of 4 g sulfasalazine and 2 g olsalazine daily during 48 wk. Of the 46 evaluable patients, 23 were assigned to sulfasalazine and 23 to olsalazine. Seven of 23 patients (30.4%) relapsed on sulfasalazine and six of 23 patients (26.1%) on olsalazine (95% confidence interval of the difference -22.0% to 30.3%). The relapse-free survival curves did not differ significantly at any time during the trial period. In both treatment groups, three patients dropped out because of adverse effects. Four patients on sulfasalazine and six patients on olsalazine experienced minor adverse effects. One patient on sulfasalazine had mild leukopenia, and four patients on sulfasalazine and one patient on olsalazine had decreased levels of haptoglobin. Thus, sulfasalazine and olsalazine are equally effective in maintaining remission of ulcerative colitis and are accompanied by a similar incidence of adverse effects.     

奥沙拉秦钠胶囊和柳氮磺胺吡啶片治疗溃疡性结肠炎的随机对照研究

目的评价奥沙拉秦钠胶囊治疗溃疡性结肠炎(UC)的临床疗效与安全性.方法采用随机对照试验,将符合入选标准的UC患者135例,分成治疗组105例,对照组30例.治疗组奥沙拉秦钠胶囊1 g,3次/d,餐中服用;对照组柳氮磺胺吡啶片(SASP)1.0 g,4次/d,餐后服用;疗程均为4周.结果治疗组和对照组的临床疗效分别为86.0%和76.7%.腹泻、腹痛、黏液血便总有效率,在治疗组中分别为85.6%、91.3%、92.5%;对照组中分别为84.0%、90.0%、68.0%.黏液血便改善治疗组较对照组为优(P＜0.05).结肠镜下疗效观察治疗组显著优于对照组(P＜0 01),其有效率分别为79.4%和42.9%.治疗组不良反应以腹泻最常见(20.0%),有5例在治疗初期因腹泻加重而中途退出.其次为恶心、上腹不适、皮疹等.对照组以白细胞减少多见(33.3%),其次为恶心、皮疹、上腹不适等.结论奥沙拉秦钠胶囊治疗UC是一种安全有效的药物.     

Effect of disodium azodisalicylate on electrolyte transport in rabbit ileum and colon in vitro. Comparison with sulfasalazine and 5-aminosalicylic acid

Azodisalicylate, used to treat ulcerative colitis, causes diarrhea in up to 12.5% of patients. We compared the in vitro effects of azodisalicylate, sulfasalazine, and 5-aminosalicylic acid on rabbit intestinal electrolyte transport. Distal ileal mucosae mounted in Ussing chambers were exposed to varying concentrations of the drugs. Mucosal addition of azodisalicylate (greater than 5 mM) caused the greatest anion-dependent increase in short-circuit current of 83 microA/cm2 (ED50 = 0.3 mM). Isotope flux measurements suggest that azodisalicylate may stimulate predominantly electrogenic HCO3 secretion and induces net NaCl secretion. In contrast, serosal addition of azodisalicylate and sulfasalazine (greater than 5 mM) decreased short-circuit current, and 5-aminosalicylic acid had no effect. Azodisalicylate had no effect on ion transport in distal colon. The effects of azodisalicylate in ileum were not inhibited with piroxicam (an inhibitor of cyclooxygenase). Mucosal cyclic adenosine monophosphate and cyclic guanosine monophosphate levels were unchanged after ileal exposure to azodisalicylate. Azodisalicylate appears to be a mechanistically unusual secretagogue, possibly explaining the increased incidence of diarrhea seen in patients taking the drug.     

Cardiomyopathy and pericardial tamponade in ulcerative colitis.

Cardiac complications of inflammatory bowel disease are rare; the most commonly reported complication is pericarditis. Drugs containing 5-aminosalicylic acid have been implicated as the cause of pericarditis in inflammatory bowel disease. A male patient with ulcerative colitis who was not taking any 5-aminosalicylic acid-containing drugs, but who developed a severe myopericarditis mimicking an acute myocardial infarction, is described. He subsequently required therapeutic pericardiocentesis for his worsening cardiac tamponade. The literature on cardiac complications of inflammatory bowel disease is reviewed.     

Sulfasalazine and 5-aminosalicylic acid inhibit contractile leukotriene formation

Sulfasalazine, used therapeutically in the treatment of ulcerative colitis, is cleaved in vivo to form 5-aminosalicylic acid (5-ASA) and sulfapyridine. In an isolated preparation of rat peritoneal cells both sulfasalazine (IC50 = 0.15 mM) and 5-ASA (IC50 = 2.3 mM), but not sulfapyridine, inhibited calcium ionophore-stimulated formation of contractile leukotriene activity. This activity, although not identified directly, is attributable to a mixture of leukotriene C4 and leukotriene D4 (commonly referred to as SRS-A, or slow-reacting substance of anaphylaxis). Reference compounds evinced expected activities (IC50 = 0.024 mM for phenidone, IC50 = 0.3 microM for nordihydroguaiaretic acid, IC50 = 0.033 mM for BW 755C), whereas para-aminosalicylic acid and thiosalicylic acid were inactive. These properties of sulfasalazine may contribute to its therapeutic efficacy in vivo.