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Olsalazine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Inflammatory Bowel Disease

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Summary

Synopsis

Olsalazine (sodium azodisalicylate; azodisal sodium) is an anti- inflammatory agent designed to deliver its active moiety, mesalazine (5- aminosalicylic acid; mesalamine), to the colon while avoiding the adverse effects associated with the use of a sulfapyridine carrier. As a prodrug, olsalazine is an effective oral treatment for both active ulcerative colitis and for maintenance of disease remission and may possibly be of benefit in patients with Crohn ’s colitis. Findings from both short and long term noncomparative and comparative studies demonstrate that olsalazine 1 to 3g daily in divided doses improves clinical signs and symptoms of colitis in approximately 60 to 80% of patients with acute ulcerative colitis of mild to moderate severity. This improvement rate was similar to that obtained with sulfasalazine, Lower doses of olsalazine, usually lg daily in divided doses, also maintained remission in patients with chronic ulcerative colitis.

While olsalazine effectively delivers mesalazine to the colon, the prodrug itself increases net luminal water secretion and accelerates gastrointestinal transit of a meal The resulting diarrhoea (occurring in approximately 17% of patients and resulting in withdrawal from therapy in 6% of patients) is distinguishable from that associated with inflammatory bowel disease by the high water content and the absence of blood. Olsalazine- induced diarrhoea usually occurred soon after initiation of olsalazine therapy or dosage increase, was more frequent with higher doses and was usually transient. Dosage reduction, increases in frequency of dosing and concomitant administration with food reduced the severity in many patients with persistent olsalazine- induced diarrhoea. With the exception of diarrhoea, olsalazine was generally well tolerated. Fewer than 14% of patients allergic to or intolerant of sulfasalazine had similar reactions to olsalazine.

Olsalazine appears to be a suitable therapy for the treatment of first attacks as well as acute exacerbation of mild to moderate acute ulcerative colitis, and for the maintenance of remission in patients with chronic ulcerative colitis.

Pharmacodynamic Properties

Olsalazine is a prodrug consisting of 2 mesalazine moieties bridged by an azo bond; the release of mesalazine is effected in the colon by bacterial cleavage of the azo bond. The protective effects of mesalazine against the pathophysiological changes in experimental colitis vary with the animal model investigated. Perfusion of the colon with mesalazine 5 mmol/L, in common with sulfasalazine 1.5 mmol/L, reversed the net increase in water and chloride secretion and the decrease in sodium absorption seen in the colon of guinea-pigs with dinitrochlorobenzene-induced colitis. However, mesalazine failed to reduce caecal ulceration in guinea-pigs with carrageenan-induced colitis. In both animal studies and in vivo perfusion studies in humans olsalazine (⩽ 2.89 mmol/ L and 6 to 11.5 mmol/L, respectively) impaired net absorption of chloride, sodium and water in the ileal and colonic mucosa; in humans this absorption may be reversed to a net secretion. At high doses (60 to 120 mg/kg) olsalazine decreased small bowel transit time in the rat. Olsalazine 1g daily decreased whole gut transit time by approximately 40% in patients with ulcerative colitis. A single oral dose of olsalazine 2g had no effect on small bowel migratory complex frequency but caused diarrhoea in 30% of healthy volunteers. Thus, some effects of olsalazine may initially aggravate the diarrhoea associated with inflammatory bowel disease.

The precise aetiology of inflammatory bowel disease and the mechanism of action of mesalazine in alleviating this condition is unclear. Speculation that cyclo-oxygenase-derived products of arachidonic acid metabolism may have a role in the pathogenesis of inflammatory bowel disease is supported by evidence that the elevated mucosal prostaglandin E2 levels associated with this condition return towards normal on subsidence of inflammation during treatment with olsalazine. Olsalazine and sulfasalazine inhibited in vitro migration of intestinal macrophages (potent producers of eicosanoids and oxygen free radicals) in response to leukotriene B4, a lipoxygenase-derived product of arachidonic acid metabolism whose release into the rectal lumen is elevated in ulcerative colitis. Hence, olsalazine may limit intestinal inflammation by restricting macrophage migration to inflamed intestinal mucosa. It has also been suggested that both olsalazine and mesalazine may act as free radical scavengers and that mesalazine may additionally suppress fatty acid peroxidation.

Pharmacokinetics

Olsalazine has very low systemic bioavailability, with less than 5% of an orally administered dose being absorbed. Once absorbed, a small proportion (≈10%) of olsalazine is conjugated to form olsalazine-O-sulphate. Olsalazine has a plasma elimination half-life of approximately 1 hour and the conjugate has a half-life of approximately 7 days.

Olsalazine is metabolised by azoreductase-containing bacteria in the colon, releasing mesalazine. Less than 5% of an oral dose (0.25 to 2g) was recovered unchanged in the faeces of either patients with ulcerative colitis or healthy volunteers. However, decreasing the whole gut transit time by approximately 50% resulted in more than 50% of the oral dose being excreted as unchanged olsalazine. Following oral administration of therapeutic doses of olsalazine (1 to 4 g/ day) to patients with ulcerative colitis intraluminal concentrations of olsalazine and mesalazine ranged from 0.04 to 0.14 g/L and 0.8 to 3.5 g/L, respectively.

The mesalazine molecule is rapidly acetylated to acetyl-mesalazine by the colonic epithelium. The extent of acetylation is dependent on transit time. Both mesalazine and acetyl-mesalazine are absorbed from the colon and excreted in the urine along with olsalazine and olsalazine-O-sulphate. Patients treated with oral olsalazine 2g daily had mean plasma mesalazine and acetylmesalazine concentrations of 0.17 to 0.38 mg/L and 0.76 to 1.4 mg/L, respectively. Low concentrations of olsalazine have been detected in the bile following both intrajejunal and intravenous administration. Olsalazine and its 2 identified metabolites are excreted in the faeces and urine in patients with inflammatory bowel disease; 17 to 31% of an oral dose of olsalazine was recovered in the urine and 47 to 53% in the faeces, as either mesalazine or acetyl-mesalazine.

Therapeutic Use

Orally administered olsalazine has been used in the treatment of acute attacks and relapse of chronic inflammatory bowel disease of varying severity, and as maintenance therapy for patients in remission. Most trials evaluated efficacy according to symptomatic improvement, histological findings and sigmoidoscopic appearances. Noncomparative studies showed that oral olsalazine 1 to 3g daily, administered for up to 3 months, improved clinical symptoms in 54 to 66% of patients with mild to severe active ulcerative colitis, and induced disease remission in 28% of patients.

Similar rates of overall clinical improvement (58 to 65%) have been achieved during long term (6 months to 2 years) oral administration of olsalazine 0.75 to 4g daily in patients with active ulcerative colitis, including patients allergic to, or intolerant of, sulfasalazine. Oral olsalazine therapy has also proved beneficial for the maintenance of remission. Remission has been maintained in 63 to 88% of patients treated for 6 to 24 months, although for those patients refractory to previous sulfasalazine therapy the remission rate was lower. However, both patients tolerant to and intolerant of sulfasalazine therapy had similar high response rates (65 to 88%) with olsalazine.

Oral olsalazine 0.75 to 3g daily for 2 to 4 weeks was superior to placebo in producing clinical improvements in patients with mild to severe ulcerative colitis. Olsalazine lg daily for 6 months was significantly better than placebo in maintaining remission of disease in patients intolerant of, or allergic to, sulfasalazine. Oral olsalazine (1 to 3g daily) appeared to be as effective as sulfasalazine (3g daily) in the short term treatment of ulcerative colitis, producing symptomatic improvement in 80%, sigmoidoscopic improvement in 80%, and histological improvement in 45% of patients during their first attack of distal colitis, and an overall improvement in approximately 40 to 60% of patients with mild to moderate active chronic colitis. However, olsalazine was better tolerated than sulfasalazine. Oral olsalazine lg daily was as effective as sulfasalazine lg daily in maintaining remission of ulcerative colitis (80 to 88% remission rate over a 6-month period). There is also some evidence that olsalazine may be of benefit in patients with Crohn’s colitis.

Tolerability

The most frequent adverse event noted during treatment with oral olsalazine was diarrhoea, which occurred in approximately 17% of patients. This diarrhoea, which was usually transient and distinguishable from that associated with inflammatory bowel disease by its high water content and the absence of blood, was associated with higher doses and usually occurred on initiation of therapy or dosage increase. For many patients it was controlled by olsalazine dosage reduction or concomitant loperamide therapy. In the remaining patients (approximately 6%) drug withdrawal was necessary.

Other reported adverse effects of olsalazine, including headache, nausea, abdominal pain, rash, dizziness and joint pain, occurred with variable frequency but resulted in olsalazine withdrawal in less than 2% of patients. The total incidence of headache, nausea, dizziness and diarrhoea associated with olsalazine (up to 13%) was similar to that seen with placebo in patients with ulcerative colitis.

Most patients allergic to, or intolerant of, sulfasalazine tolerated olsalazine. The incidence of olsalazine-induced diarrhoea in these patients was 8 to 15%. Allergic or gastrointestinal symptoms occurred in up to 14% of these patients, and were more frequent in those who had shown severe allergic or gastrointestinal reactions to sulfasalazine. Male infertility resulting from sulfasalazine therapy improved after substitution with olsalazine.

Dosage and Administration

The usual oral dose of olsalazine for treating active exacerbation of inflammatory bowel disease is 1 to 3g daily in divided doses administered with food, although doses of up to 4g daily have been used. Lower doses, usually lg daily, should be used for maintenance of remission in patients with chronic ulcerative colitis. Patients who have had severe allergic reactions to sulfasalazine should be monitored for similar manifestations when started on olsalazine therapy.

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    Alison N. Wadworth & Andrew Fitton

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  1. Alison N. Wadworth
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Various sections of the manuscript reviewed by: S. Bank, Division of Gastroenterology, Long Island Jewish Medical Center, New York, New York, USA; G. Courtney, St Thomas’ Hospital, London, England; G.Järnerot, Division of Gastroenterology, Orebo Medical Center Hospital, Orebo, Sweden; D.P. Jewell, Gastroenterology Unit, Radcliffe Infirmary, Oxford, England; U. Klotz, Dr Margarete Fischer-Bosch-Institut Für Klinische Pharmakologie, Stuttgart, Federal Republic of Germany; K. Lauritsen, Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; S. Meyers, The Mount Sinai School of Medicine, New York, New York, USA; O.H. Nielsen, Department of Medical Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; K. Ohe, Health Care Center, University of Occupational and Environmental Health, Japan School of Medicine, Kitakyushu, Japan; S. Rao, Gastrointestinal Unit, Royal Hallamshire Hospital, Sheffield, England; S.A. Riley, Department of Medicine, Hope Hospital School of Medicine, University of Manchester, Salford, England; K.W. Schroeder, Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

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Wadworth, A.N., Fitton, A. Olsalazine. Drugs 41, 647–664 (1991). https://doi.org/10.2165/00003495-199141040-00009

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