Br. J. clin. Pharmac. (1992), 34, 189-198

Drug therapy of ulcerative colitis B. CROTIY & D. P. JEWELL Gastroenterology Unit, Radcliffe

Infirmary, Oxford OX2 6HE

Introduction

These have been shown to have less effect on plasma cortisol concentrations and to have similar response rates (Kumana et al., 1982; McIntyre et al., 1985; Multicentre Trial, 1971). The mechanism of action of corticosteroids in ulcerative colitis is incompletely understood. However, they are known to have multiple effects on the immune system and the inflammatory response. These include decreased capillary permeability, impaired monocyte and neutrophil chemotaxis and phagocytosis, inhibition of production of cytokines such as IL-1, TNFa and IL6, reduced lymphocyte cytotoxicity, stabilization of lysosomes and reduction of eicosanoid and platelet activating factor production by inhibition of phospholipase A2 (Hawthorne & Hawkey, 1989).

The management of patients with ulcerative colitis has been well established since the trials of corticosteroids and sulphasalazine in the 1950s and 60s. However, the last decade has seen the introduction of a variety of new steroids, salicylates, immunosuppressive agents and other compounds directed against specific inflammatory mediators. In this review we will attempt to define the place of the many drugs now used in ulcerative colitis.

Corticosteroids

Oral corticosteroids were first used in ulcerative colitis in the early 1950s. In 1955 the efficacy of cortisone was proven in a large placebo controlled trial (Truelove & Witts, 1954, 1955) and this was soon followed by the demonstration of a dose-response effect (Baron et al., 1962a). Intramuscular or intravenous ACTH has also been used in some centres and there is some evidence that it may be superior in acute colitics who have not previously been given steroids (Meyers et al., 1983). Oral cortisone (Truelove & Witts, 1959) and prednisolone (Lennard-Jones et al., 1965) have both been shown to be ineffective in maintaining remission. Topical steroids were introduced soon afterwards and another controlled trial demonstrated the superiority of hydrocortisone enemas over placebo (Truelove, 1958). The combination of oral and topical therapy was also shown to be highly effective (Truelove, 1960). Since that time oral, intravenous and topical steroids have been the first line treatment for ulcerative colitis and have made a major contribution to the decline in mortality due to severe attacks (from 35% to less than 1% in Oxford over the last 30 years (Jewell, 1989)). Topical steroids can be administered as 100 ml enemas, 5 ml foams or suppositories. Enemas have been shown to spread at least as far as the descending colon (Matts & Gaskell, 1961; Swarbrick et al., 1974) and the foam preparation to the sigmoid colon (Farthing et al., 1979). The demonstration of systemic absorption after rectal prednisolone and hydrocortisone (Farmer & Schumacher, 1970; Powell-Tuck et al., 1976; Spencer et al., 1960) has stimulated the development of enemas containing poorly absorbed compounds such as prednisolone metasulphobenzoate, betamethasone valerate and beclomethasone.

New steroids In recent years several new steroids with low systemic bioavailability have been developed in an attempt to reduce the risk of side-effects. Tixocortol pivalate is derived from cortisol, the 21-hydroxyl group being replaced by a thiol group esterified to pivalic acid. This compound is absorbed but avid hepatic first pass metabolism ensures that plasma cortisol levels are unaffected (Larochelle et al., 1983). When used as an enema it is as effective as hydrocortisone (Hanauer et al., 1986). Budesonide is a non-halogenated steroid which is structurally related to 16ao-hydroxyprednisolone. A Swedish trial comparing budesonide and prednisolone21-phosphate enemas demonstrated equal clinical efficacy, although sigmoidoscopic and histological improvement were greater with budesonide (Danielsson et al., 1987). Budesonide did not affect serum cortisol concentrations. A multicentre trial of oral budesonide in Crohn's disease is in progress. Fluticasone is a fluorinated steroid which is both poorly absorbed and subject to a high first pass metabolism. This compound has been primarily developed for topical use in asthma but its pharmacokinetic profile is very promising for inflammatory bowel disease. Unfortunately it proved disappointing in a placebo controlled trial in left sided ulcerative colitis (Angus et al., 1992). Multicentre trials of fluticasone in ulcerative colitis and Crohn's disease have recently been completed and the results are awaited with interest.

Correspondence: Dr D. P. Jewell, Gastroenterology Unit, Radcliffe Infirmary, Oxford OX2 6HE

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Salicylates

Sulphasalazine Sulphasalazine (5-aminosalicylic acid (SASA) linked to sulphapyridine by an azo bond) was developed in the 1930s for use in arthritis. Its development was based on the idea that the combination of an antibiotic and a salicylate might be efficacious in a condition then thought to have an infectious aetiology and known to respond to aspirin. Results of trials in arthritis were disappointing but an unexpected symptomatic improvement in patients with ulcerative colitis led to its wider use in this condition (Svartz, 1988). In the 1980s the role of sulphasalazine in rheumatoid arthritis was re-evaluated and it has become widely used following controlled trials demonstrating its efficacy (Neumann et al., 1983; Pullar et al., 1983). In 1962 a controlled trial showed that sulphasalazine was more effective than placebo in the treatment of mild relapses of ulcerative colitis (Baron et al., 1962b), although studies at about the same time demonstrated that corticosteroids were superior (Lennard-Jones et al., 1960; Truelove et al., 1962). However, in 1965 the first placebo controlled maintenance trial demonstrated a 21% relapse rate over 1 year in patients taking sulphasalazine compared with 73% with placebo (Misiewicz et al., 1965) and since then it has been used routinely to maintain remission. As only 10-20% of sulphasalazine is absorbed in the small intestine, the majority of an orally ingested dose is delivered intact to the colon. Most of the absorbed sulphasalazine is excreted in bile without modification (Das et al., 1979). Once in the colon the drug undergoes bacterial reduction releasing SASA and sulphapyridine (Peppercorn & Goldman, 1972). Virtually all the sulphapyridine is absorbed and metabolised in the liver by acetylation, hydroxylation and glucuronidation (Schroder & Campbell, 1972). The rate of metabolism varies according to acetylator status and slow acetylators have a higher rate of sulphapyridine induced side effects (Das et al., 1973). Jejunal absorption of 5ASA is rapid and complete (Nielson & Bondesen, 1983) but colonic absorption is very limited. The vast majority of SASA delivered to the colon is excreted unchanged in the faeces or metabolised by a non-polymorphic N-acetyl transferase. The primary site of acetylation is the colonic epithelium (Allgayer et al., 1989; Ireland et al., 1990) and the acetylated metabolite is excreted in the stool and the urine (Peppercorn & Goldman, 1973). In the 1970s Azad Khan and Truelove demonstrated that SASA was the active moiety of sulphasalazine by comparing the response to sulphasalazine, sulphapyridine and SASA enemas in patients with mildly active distal colitis (Azad Khan et al., 1977). This finding has subsequently been confirmed by others (Klotz et al., 1980; Van Hees et al., 1980). In contrast sulphapyridine appears to be the active agent in rheumatoid arthritis (Neumann et al., 1986). Studies of rectal installation of N-acetyl SASA have failed to show any clinical effect (Binder et al., 1981 a,b; Van Hogezand et al., 1988; Willoughby et al., 1980a), although one group reported sigmoidoscopic and histological improvement (Willoughby et al., 1980a).

The mode of action of SASA in inflammatory bowel disease is unknown. However, the disposition of oral SASA containing compounds and the response to enemas both indicate that the site of action is the colonic mucosa. Luminal concentrations of SASA and N-acetyl 5ASA in patients taking maintenance doses are about 10 mM (Lauritson et al., 1984). Thus it is perhaps not surprising that a wide range of pharmacological effects have been observed and proposed as possible mechanisms of action. These include inhibition of prostaglandins (Hawkey & Truelove, 1983), leukotrienes (Stenson & Lobos, 1982) or platelet activating factor (Eliakim et al., 1988); free radical scavenging (Miyachi et al., 1987); inhibition of neutrophil, macrophage or mast cell function (Barrett et al., 1985; Stenson et al., 1984); alteration of colonic permeability (von Ritter et al., 1989); inhibition of humoral immunity (MacDermott et al., 1989); and inhibition of production (Mahida et al., 1991) or action (Crotty et al., 1991, 1992) of cytokines. In a number of experimental systems the effects of sulphasalazine, SASA, sulphapyridine and 4ASA differ. This subject has recently been reviewed (Ireland & Jewell, 1990).

Adverse effects Adverse effects are common in patients taking sulphasalazine and necessitate stopping the drug in about 10% of patients (Taffet & Das, 1983). They are predominantly due to sulphapyridine and tend to occur in the first few months of therapy. The commonest are dose-related, especially at daily doses greater than 2 g (Azad Khan et al., 1980), and are more frequent in slow acetylators (Azad Khan et al., 1980; Das et al., 1973). These include nausea and vomiting, abdominal pain, anorexia, headache, macrocytosis, reticulocytosis (rarely haemolytic anaemia with Heinz bodies), cyanotic skin discoloration and impaired male fertility due to oligospermia and reduced sperm motility (Azad Khan et al., 1980; Das, 1989; Taffet & Das, 1983). An enteric coated preparation may be useful in patients with gastrointestinal side effects. All are reversible on withdrawal of the drug. Idiosyncratic adverse effects are less common and include skin rashes (occasionally with photosensitivity), agranulocytosis and other blood dyscrasias, alopecia, fibrosing alveolitis, eosinophilic pneumonitis, a range of hepatic injuries, peripheral neuropathy and a lupus-like syndrome. Folate deficiency can occur but is seldom of clinical significance in the absence of other causes. Rarely sulphasalazine can lead to an exacerbation of colitis (Azad Khan et al., 1980; Das, 1989; Taffet & Das, 1983). A small minority of adverse effects are attributable to SASA, most commonly diarrhoea (Austin et al., 1984). Care should be taken in patients who are sensitive to aspirin. Recently there has been concern over possible renal damage following nine British reports of nephrotoxicity in patients taking 5ASA as Asacol (Committee on Safety of Medicines, 1990). Animal studies have demonstrated that SASA is nephrotoxic to rats when given in high doses (Calder et al., 1972). There are also reports from other countries of renal toxicity due to Asacol (Novis et al., 1988) and Claversal (von Muhlendahl, 1989). As discussed below, there is some evidence that this problem may be due to higher serum SASA concentrations with these preparations.

Drug therapy of ulcerative colitis The new salicylates As most of the adverse effects of sulphasalazine are due to the sulphapyridine moiety, a number of other methods have been developed to deliver 5ASA to the colon

(Thomson, 1991). Olsalazine Olsalazine is two molecules of 5ASA joined by an azo bond. Like sulphasalazine it is poorly absorbed in the small intestine and broken down in the colon by bacterial reduction (Lauritsen et al., 1984; Sandberg-Gertzen et al., 1983; Willoughby et al., 1982). The drug is well tolerated by patients previously intolerant of sulphasalazine (Ireland & Jewell, 1987; SandbergGertzen et al., 1986) and has been shown to be as effective as sulphasalazine in the treatment of mild attacks (Ewe et al., 1988; Rao et al., 1989; Willoughby et al., 1988) and in maintenance of remission (Ireland et al., 1988). It is less effective when given per rectum (Selby et al., 1985). The commonest side effect is watery diarrhoea which occurs in about 15% of patients (Sandberg-Gertzen et al., 1986) and is due to alteration of small bowel fluid absorption by the parent molecule (Mohsen et al., 1987; Raimundo et al., 1991). The diarrhoea tends to improve with time and can often be overcome by a temporary lowering of the dose (Lauritsen et al., 1988). However, it remains a common cause of stopping the drug. Mesalazine Mesalazine is the generic name given to all enteric coated and slow release preparations where 5ASA is not bound to another compound. (i) Enteric coated 5ASA Several enteric coated preparations have been developed. Asacol is coated with Eudragit S, a pH sensitive, acrylic based resin, which dissolves when luminal pH is above 7, leading to release of SASA in the terminal ileum and proximal colon (Dew et al., 1983a). Claversal and Salofalk, neither licensed for use in the U.K., are 5ASA compressed with sodium bicarbonate and glycine, coated with a similar resin, Eudragit L, which allows release of 5ASA when pH rises above 6 (Klotz et al., 1985). Asacol is well tolerated by patients unable to take sulphasalazine (Dew et al., 1983b) and controlled trials have demonstrated that it is as effective as sulphasalazine in the treatment of active colitis (Riley et al., 1988a) and in maintaining remission (Riley et al., 1988b). Claversal has also been shown to have similar efficacy to sulphasalazine in active disease (Rachmilewitz, 1988) and remission (Rutgeerts, 1988). (ii) Slow release 5ASA Pentasa tablets (and Rowasa in USA) contain granules of SASA coated with a semipermeable ethyl cellulose membrane which gradually releases SASA, although at an increased rate when pH is above 6 (Rasmussen et al., 1982). Like Asacol and olsalazine, the drug is well tolerated by patients unable to take sulphasalazine (Mulder et al., 1988a) and has been shown to be as effective as sulphasalazine in maintaining remission (Mulder et al., 1988b). An uncontrolled study of Pentasa in active disease has reported similar response rates to other SASA containing compounds (Hanauer et al., 1989). 5ASA pharmacokinetics All of these salicylates employ methods to prevent SASA release in the upper gastrointestinal tract so that absorption from the small bowel

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is kept to a minimum and a high percentage of the ingested dose is delivered to the colon. Once released in the intestinal lumen, SASA can be absorbed, metabolised or excreted in the faeces. Animal data suggest that gut wall N-acetylation is capacity limited (Pieniaszek & Bates, 1979) and this is supported by a decreasing proportion of acetylated SASA in the faeces of patients on increasing doses of olsalazine (Lauritsen et al., 1984). In ulcerative colitics taking equimolar doses of olsalazine, Asacol, Salofalk or Pentasa the lowest peak serum SASA concentrations were seen with olsalazine. Concentrations were marginally higher with Pentasa and significantly higher with Asacol and Salofalk (Laursen et al., 1990a). Studies of volunteers have reported lower SASA levels after taking Pentasa than after Asacol or Claversal (Christensen et al., 1990) and lower concentrations after sulphasalazine than after Claversal (Norlander et al., 1989) or Asacol (Dew et al., 1984). There is virtually no luminal SASA release in ileostomates taking sulphasalazine (Das et al., 1979) or olsalazine (Sandberg-Gertzen et al., 1983), in contrast to mesalazine (Christensen et al., 1990; Dew et al., 1983a; Rasmussen et al., 1982). Taken together these studies suggest that azo-bonded drugs are delivered intact to the colon whereas the mesalazine preparations release varying amounts of SASA in the small intestine, some of which is absorbed and some acetylated. The relatively low serum SASA levels and high faecal metabolite levels reported in individuals taking Pentasa are consistent with a more gradual release allowing for more complete metabolism by the capacity limited intestinal N-acetyl transferase. These differences may have some clinical significance in the light of the recent reports of nephrotoxicity in patients taking Asacol (Committee on Safety of Medicines, 1990; Novis et al., 1988) and or Claversal (von Muhlendahl, 1989).

Topical 5ASA and 4ASA The first report of the use of rectal salicylates in ulcerative colitis was the study of Azad Khan and Truelove which demonstrated that SASA was the active component of sulphasalazine. Patients with active distal colitis improved when treated with 5ASA or sulphasalazine enemas but not with sulphapyridine (Azad Khan et al., 1977). Retrograde spread to the splenic flexure occurs in the majority of patients using 100 ml enemas (Campieri et al., 1986) and subsequent studies have confirmed that topical SASA is superior to placebo (Campieri et al. 1984a, 1991; Willoughby et al., 1986)) and at least as effective as rectal steroids (Campieri et al., 1981; Danish SASA Group, 1987). Preparations containing 1 to 4 g are available but response rates are not improved by the use of higher doses (Campieri et al., 1991). Topical SASA is often useful in patients with resistant proctitis, although therapy may need to be continued for 2 to 3 months before a response is seen and relapse rates are high (Guarino et al., 1987; Hanauer & Schultz, 1987). Nightly enemas have been used as maintenance therapy in distal colitis (Biddle et al., 1988). Rectal 4ASA has also been demonstrated to be superior to placebo (Ginsberg et al., 1988; Gondolfo et al., 1987; Selby et al., 1984) and as effective as topical

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5ASA (Campieri et al., 1984b) in distal disease. A preliminary report suggests that 4ASA may be useful as an enteric coated tablet (Ginsberg & Albert, 1988). Its lack of free radical scavenging activity and differing pattern of effects on prostaglandin metabolism raise interesting questions about the mode of action of the salicylates (Nielson & Ahnfelt-Ronne, 1988).

Immunosuppressive agents

Azathioprine and 6-mercaptopurine Azathioprine is converted to 6-mercaptopurine and then to thioinosinic acid by hypoxanthine guanine phosphoribosyl transferase. Thioinosinic acid impairs purine biosynthesis and interconversion, thus inhibiting cell proliferation. However, it is not clear that this is the mechanism of action at lower doses, such as those used in inflammatory bowel disease and there is evidence that these drugs do have other immunomodulatory effects (Hawthrone & Hawkey, 1989). The available data do not support the use of azathioprine in acute relapses of ulcerative colitis. A placebo controlled study conducted in Oxford showed no benefit, although the duration of the trial may have been too short to show an effect (Jewell & Truelove, 1974). A smaller Italian study reported no difference between azathioprine and sulphasalazine (Caprilli et al., 1975). However, azathioprine does have a role in the treatment of chronic active disease and two large studies have shown it to be an effective steroid sparing agent in these patients (Kirk & Lennard-Jones, 1982; Rosenberg etal., 1975). Both reported a slow onset of action and azathioprine or 6-mercaptopurine should be continued for at least 3 months before they are deemed to be ineffective. There is also mounting evidence that azathioprine and 6-mercaptopurine may be effective maintenance therapy. The preliminary results of a study of withdrawal of azathioprine in a group of patients on the drug for at least 6 months demonstrate a lower rate of relapse when azathioprine is continued (Hawthorne et al., 1991). An earlier study failed to show any benefit in patients continuing on the drug after control of an acute attack, although there was a strong beneficial trend in those with previously established disease (Jewell & Truelove, 1974). A large uncontrolled American series has reported that 73% of patients with refractory ulcerative colitis have remained in remission for at least 2 years while taking 6-mercaptopurine in contrast to a relapse rate of 77% in the 12 months after stopping the drug (Present et al., 1988). Azathioprine and 6-mercaptopurine are associated with a significant number of adverse effects. The most important is bone marrow depression, which is dose related. This is uncommon at the usual dose of 2-2.5 mg kg-' but regular blood counts are essential, especially at the beginning of therapy. Other adverse effects include nausea, pancreatitis, fever, arthralgia, diarrhoea, skin rashes and hepatic reactions (Present et al., 1989). Patients of reproductive age are generally advised to use contraceptives, although the available data do not suggest an increased rate of foetal abnormalities (Bear,

1976; Hou, 1985; Present et al., 1989). Despite the high rate of lymphoma and skin cancer seen in transplant recipients taking immunosuppressive drugs, a prospective survey of 1109 non-transplant patients on azathioprine showed a relatively modest 1.6 fold increase in the risk of cancer (Kinlen et al., 1979). Other series have also reported a relatively low level of risk (Present et al., 1988; Tage-Jensen et al., 1987).

Cyclosporin Cyclosporin is a fungal undecapeptide which impairs activation of lymphocytes and macrophages by inhibiting the production of interleukin-2 and other cytokines. The mechanism is incompletely understood but is thought to be related to cytoplasmic binding to cyclophilin, a peptidyl-prolyl isomerase, and inhibition of its rotamase activity (Schreiber, 1991). Oral cyclosporin has been shown to be effective in the treatment of active Crohn's disease (Brynskov et al., 1989a) and evidence of its activity in ulcerative colitis is growing (Hodgson, 1991). In an open study colectomy was avoided in 73% of patients given intravenous cyclosporin after failing to respond to 10 days of intravenous steroids (Lichtiger & Present, 1990). A controlled trial is in progress. A preliminary report has also suggested a role for rectal cyclosporin in refractory left-sided colitis. There was negligible systemic absorption (Brynskov et al., 1989b). In contrast to azathioprine, the responses to cyclosporin occurred within a few days in these studies. The more potent FK506 has not yet been used in inflammatory bowel disease. Methotrexate Recent experience with low dose methotrexate in patients with refractory ulcerative colitis or Crohn's disease has also been quite encouraging. An open study reported a 79% rate of significant clinical improvement after 12 weeks of weekly intramuscular methotrexate (Kozarek et al., 1989, 1990). The responders switched to a weekly oral dose and 70% were still in remission after 1 year. There is minimal immunosuppression at the doses used, suggesting that methotrexate is acting as an antiinflammatory agent rather than by folic acid antagonism (Anderson et al., 1985). Interestingly, there are structural similarities to interleukin-1 (Dinarello, 1989). A controlled trial seems warranted.

Antibiotics

Although a definite role for metronidazole has been established in Crohn's disease, particularly for peri-anal disease (Bernstein et al., 1981; Brandt et al., 1982; Ursing et al., 1982), studies of the use of antibiotics in ulcerative colitis have been disappointing. Controlled trials of intravenous metronidazole (Chapman et al., 1986) and oral vancomycin (Dickinson et al., 1985) have not provided any support for their use. Obviously they are indicated for colonic perforation or other infective complications.

Drug therapy of ulcerative colitis Drugs under investigation A better understanding of the immunological mechanisms and multiple inflammatory mediators involved in inflammatory bowel disease (Podolsky, 1991) has led to investigation of several new agents in an attempt to control the inflammatory process. Studies of eicosanoids in the inflamed mucosa have revealed that the concentration of the potent neutrophil chemoattractant, leukotriene B (LTB4), is elevated in inflammatory bowel disease (Lauritsen et al., 1986). LTB4 concentrations were lowered by the lipoxygenase inhibitor, zileuton (Laursen, 1990b) but the preliminary findings of a controlled trial in active ulcerative colitis were that improvement only occurred in patients not

taking sulphasalazine (Stenson et al., 1991a). LTB4 receptor antagonists (Fretland et al., 1990) and thromboxane synthetase inhibitors (Banerjee & Peters, 1990) are also under investigation. LTB4 concentrations are also lowered by ingestion of omega-3 fatty acids such as eicosapentaenoic acid which is a component of fish oil. These compounds replace arachidonic acid in cell membranes and are similarly released by phospholipase A2. Eicosapentanoic acid is a poor substrate for the cyclooxygenase pathway but competes with arachidonic acid for the lipoxygenase enzyme to produce leukotriene B5 instead of LTB4. LTB5 is a much less potent stimulator of neutrophils (Lee et al., 1985; Prescott, 1984). Preliminary reports of two clinical trials of fish oil in ulcerative colitis have provided conflicting results (Hawthrone et al., 1990; Stenson et al., 1991b). Platelet activating factor (PAF), another lipid mediator released from membrane lipids by phospholipase A2, is also known to be present in increased concentration in the colonic mucosa of patients with active ulcerative colitis (Eliakim et al., 1988). Its effects can be antagonized by PAF receptor antagonists (Wallace etal., 1987) and a controlled trial is in progress. Mast cells contain a large number of inflammatory mediators and are commonly present in the inflamed intestine of patients with ulcerative colitis. It has become clear that mast cells are heterogeneous and that intestinal mast cells differ from mast cells in other sites (Schwartz, 1988). This is consistent with the lack of response to the mast cell stabiliser, disodium cromoglycate (Binder et al., 1981; Buckall et al., 1978), which has been shown to have little activity on intestinal mast cells (Pearce et al., 1982). Ketotifen is a more specific compound and has shown promise in experimental models of colitis (Eliakim et al., 1991). The observation of increased mucosal innervation in the rectal mucosa in active ulcerative colitis has led to an uncontrolled trial of topical lignocaine (Bjork et al., 1989, 1991). There was impressive symptomatic and histological improvement but no change in the pattern of innervation. In recent years investigation of the ability of intestinal epithelial cells to act as antigen presenting cells has resulted in a great deal of interest in the role of this process in the pathogenesis of inflammatory bowel disease (Bland & Warren, 1986a,b; Mayer et al., 1987 & 1990). This has led to the suggestion that hydroxychloroquine might control mucosal inflammation by

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inhibiting lysosomal processing of antigens and thus prevent antigen presentation. Hydroxychloroquine has previously been shown to be effective in animal models of colitis (Rhodes et al., 1982). Initial results in ulcerative colitis have been encouraging (Mayer et al., 1991) and the results of a controlled trial are awaited with interest.

Treatment regimes There is no consensus about the details of the management of patients with ulcerative colitis, although the general principles are well accepted. The following regimes are currently used in Oxford and are based on a philosophy of early aggressive treatment.

Acute colitis

Distal disease Inflammation known to be limited to the distal colon is treated with local steroids in combination with sulphasalazine or one of the newer salicylates. A small proportion of these patients are very refractory and may require rectal SASA, oral steroids, rectal cyclosporin or even intravenous steroids or surgery. Some groups prefer to use rectal SASA as the initial therapy in these patients (Campieri et al., 1981; Danish SASA Group, 1987).

Mild and moderate disease Patients with up to 4 or 5 daily bowel motions without any systemic disturbance are treated with a combination of 20 mg prednisolone and steroid enemas. This is normally continued for 4 weeks and then tailed off over the next 3 to 4 weeks. In patients with more severe diarrhoea, the initial dose of prednisolone is 40 mg for a week, reducing to 30 mg for the second week, then 20 mg for a month. Severe disease Severe attacks are defined as the passage of more than 6 bloody stools daily accompanied by at least one of the following signs of systemic disturbance; temperature above 37.5° C, pulse rate above 100 beats min-', haemoglobin below 10 g dl-1 or serum albumin below 35 g dl-1 (Truelove & Witts, 1954). These patients are admitted to hospital for intravenous fluids and electrolytes and may require transfusion. They are given intravenous steroids (400 mg hydrocortisone or 64 mg methyl prednisolone daily) and twice daily rectal steroids (100 mg hydrocortisone in 100 ml over 20 to 30 min) for 5 days. No food is allowed although the need for this is disputed (Dickinson et al., 1980; McIntyre et al., 1986). Patients who respond are then allowed a light diet and commenced on 40 mg prednisolone which is tapered as above. About 20-30% of severe attacks will come to surgery despite this regime. Well established indicators of a poor prognosis include the passage of more than 9 stools, a pulse rate greater than 100 beats min- 1 or a temperature above 380 C in the first 24 h of treatment and a serum albumin below 30 g dl-1 in the first 4 days (LennardJones et al., 1975). The presence of mucosal islands (Bryan & Phillida, 1964) or multiple loops of small bowel (Chew et al., 1992) on a plain abdominal X-ray are also associated with an increased rate of surgery.

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There is no evidence that higher doses of steroids are beneficial (Rosenberg et al., 1990) but, as mentioned previously, the early reports of response to intravenous cyclosporin are encouraging. There has never been a controlled trial to examine the optimal duration of intravenous steroids, but it has been our experience that there is no point continuing medical therapy beyond 5 to 7 days. Chronic active colitis A number of patients require therapy to suppress the activity of their colitis. Many of these will come to surgery but a proportion can be controlled by 2 mg kg-1 azathioprine, occasionally combined with a low dose of oral steroids.

Maintenance therapy When active disease has been brought into remission sulphasalazine is commenced at a dose of 1 g twice daily. This is continued indefinitely. Patients intolerant of sulphasalazine and men planning a family are given

olsalazine 500 mg twice daily or one of the mesalazine preparations. Ulcerative colitis in pregnancy and childhood

Pregnant women with quiescent ulcerative colitis should continue maintenance therapy as normal. There is no evidence that sulphasalazine has any teratogenic effects. Obviously there are no therapeutic trials of ulcerative colitis in pregnancy but we believe that active inflammation should be treated aggressively. Experience in major centres suggests that steroids are safe in contrast to the deleterious effects of persistent uncontrolled activity (Baioco & Korelitz, 1984; Willoughby & Truelove, 1980). We are reluctant to use azathioprine during pregnancy, although, as previously mentioned there is no evidence of an increased rate of foetal abnormalities (Bear, 1976; Hou, 1985; Present et al., 1989). Children with ulcerative colitis should also be treated in the manner outlined above with appropriate dose reduction. Prolonged active disease is much more likely to lead to growth retardation and delayed development than its control by corticosteroids (Werlin & Grand, 1977).

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(Received 21 October 1991, accepted 25 February 1992)

Drug therapy of ulcerative colitis.

Br. J. clin. Pharmac. (1992), 34, 189-198 Drug therapy of ulcerative colitis B. CROTIY & D. P. JEWELL Gastroenterology Unit, Radcliffe Infirmary, Ox...
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