New developments in the pharmacotherapy of inflammatory bowel disease J. W. Harting Introduction For m a n y y e a r s the p h a r m a c o t h e r a p e u t i c possibilities in i n f l a m m a t o r y bowel disease (IBD) were limited to sulfasalazine and local or systemic corticosteroids. Sulfasalazine was developed at the end of the 1930s for the t r e a t m e n t of rheumatoid arthritis. At t h a t time, r h e u m a t o i d arthritis was assumed to be of bacterial origin; in addition, good clinical results were being achieved with acetylsalicylic acid. Thus, there was every reason to develop a drug t h a t combined both antibacterial and acetylsalicylic acidlike properties, and the result was sulfasalazine. More recent additions to IBD t h e r a p y include the mesalazine p r e p a r a t i o n s and olsalazine, as well as the i m m u n o s u p p r e s s a n t s azathioprine and 6mercaptopurine. This article will first discuss the clinical feat u r e s and aetiology of IBD and current p h a r m a cotherapeutic possibilities. Developments in the p h a r m a c o t h e r a p y of IBD will t h e n be reviewed: aminosalicylates, corticosteroids, immunosuppressants, lipoxygenase inhibitors, fish oil, sucralfate, b i s m u t h compounds, free radical scavengers, (hydroxy)chloroquine, sodium cromoglycate and methotrexate. W h a t is IBD? IBD is characterized by bowel i n f l a m m a t i o n involving the mucosa of the small bowel or the colon. Some authors consider only Crohn's disease and ulcerative colitis to be i n f l a m m a t o r y bowel diseases. Others also regard i n f l a m m a t i o n of the bowel as a result of bacterial, viral, fungal or parasitic infections as well as ischaemic colitis, drug (antibiotic)-induced and radiation colitis as forms of IBD. However, in this article we shall confine ourselves to aspects of Crohn's disease and ulcerative colitis. Both diseases have a number of clinical, histological and epidemiological characteristics in common. Both occur more frequently in people of Jewish descent and less frequently in blacks in the United States. The first generation of offspring of patients with IBD r u n a g r e a t e r risk of developing the dis-

ease [1]. The major s y m p t o m s of both diseases are diarrhoea, abdominal pain, fever and anorexia. Ulcerative colitis Ulcerative colitis is a chronic r e c u r r e n t inflamm a t i o n of the mucosa of the large bowel. The disease process is almost always localized in the rectum, with variable extension in continuity to the more proximal colon. Proctitis or proctosigmoiditis is regarded as a mild form of ulcerative colitis and is confined to the distal portion of the large bowel. The total n u m b e r of patients suffering from this disease is about 70 to 100 per 100,000 inhabitants. The a t t a c k r a t e in the N e t h e r l a n d s is 5 to 10 per 100,000 i n h a b i t a n t s each year. Ulcerative colitis r u n s an erratic and unpredictable course. The m a i n elements of the p a t i e n t ' s complaints are a change in the defaecation p a t t e r n and a bloody m u c o p u r u l e n t admixture. Clinically, a distinction is m a d e between such limited forms as proctitis or proctosigmoiditis and the more extensive forms of ulcerative colitis. Proctosigmoiditis is characterised by recurrent blood loss via the anus and v a r y i n g tenesmi, usually without genuine diarrhoea, emaciation or systemic manifestations. In the less severe forms of ulcerative colitis, the disease usually starts with v a g u e abdominal discomfort, general malaise and changes in the frequency and consistency of the stools. In more severe cases the disease generally starts r a t h e r abruptly with fever, bloody diarrhoea, pain, and worsening of the p a t i e n t ' s general condition together with anorexia and weight loss. The disease usually spreads diffusely from the anal ring proximally. However, in about 10 to 15% of patients the disease begins with f u l m i n a n t inv o l v e m e n t of the entire colon. As a result of the severe diarrhoea with excessive loss of water, electrolytes, protein, and blood, severe dehydration develops together with electrolyte and protein abnormalities. The clinical picture usually includes high fever, tachycardia, apathy, a tendency towards metabolic acidosis and eventually, shock.

Harting JW. New developments in the pharmacotherapy of inflammatory bowel disease. Pharm Weekbl [Sci] 1992;14(4A):275~86. Keywords Crohn's disease Inflammatory bowel disease Ulcerative colitis J. W. Harting: Oosterschelde Hospital Foundation, Goes, the Netherlands.

14(4A) 1992

Abstract In this article the clinical features and aetiology of inflammatory bowel diseases are described and current pharmacotherapeutic possibilities are explored. Also reviewed are recent developments and future prospects for the pharmacotherapy of inflammatory bowel diseases, including aminosalicylates, corticosteroids, immunosuppressants, lipoxygenase inhibitors, fish oil, sucralfate, bismuth compounds, free radical scavengers, (hydroxy)chloroquine, sodium cromoglycate and methotrexate.

Accepted June 1992.

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Crohn 's disease Crohn's disease (terminal ileitis, regional ileitis, regional enteritis, granulomatous ileocolitis) is a transmural, mainly submucosal inflammatory disease. In principle, Crohn's disease may occur anywhere in the gastro-intestinal canal, but seems to be localized mainly in the terminal ileum, the colon and the perianal region. The presence of epithelioid cellular granulomas in about 50% to 70% of patients is a histological characteristic of the disease. Its prevalence is between 20 and 50 subjects per 100,000 inhabitants, and the attack rate is about 3 to 5 per 100,000 inhabitants per year. The maximum incidence is in the 10- to 30-year-old age group, possibly with a second small peak among the elderly. Crohn's disease is characterized by an erratic course. The major clinical symptoms are abdominal pain and changes in the patient's defaecation pattern (chiefly diarrhoea). General manifestations of the disease include anorexia, emaciation, malaise, fever, anaemia, and the formation of an infiltrate in the lower right abdominal quadrant. Crohn's disease is a chronic disorder with int e r m i t t e n t periods of exacerbation. These exacerbations usually arise from infectious complications, such as confined perforation with formation of an infiltrate or internal or external fistulas. The periods of exacerbation are characterized by worsening of the patient's general condition, emaciation, fever, development of a palpable mass, and leukocytosis. In the early stage of Crohn's disease, most patients have moderately pronounced diarrhoea, sometimes ulcer-like epigastric discomfort, and not infrequently, anal pathology. In some patients the disease starts with a picture resembling acute appendicitis. When the disease is full-blown, the pattern of complaints is characterised by pain (either of the 'appendicitis type' or of the 'sub-obstruction type'), diarrhoea (usually without evidence of gross blood), fever, and ulcer-like epigastric pain. As a rule anal blood loss is less pronounced t h a n in ulcerative colitis, unless the distal rectosigmoid is frankly involved. However, chronic intestinal blood loss occurs in the majority of patients in the course of the disease. Because of the correspondence in symptoms, the differential diagnosis of ulcerative colitis and Crohn's disease is not simple. A better diagnosis can be made by endoscopy t h a n with an X-ray, and it is often possible to distinguish endoscopically between these intestinal disorders. Nevertheless, the differential diagnosis is so difficult t h a t the wrong choice is made in an estimated 10% to 20% of all patients with ulcerative colitis [2-4].

Aetiology of IBD Although the exact aetiologies of both ulcerative colitis and Crohn's disease are not known, many factors are presumed to play a role. Bacteria and viruses Bacterial and viral organisms have been mentioned as possible causes of IBD, in particular, 276

mycobacteria in Crohn's disease. Mycobacterium isolated from patients with Crohn's disease has been found to be biochemically and genetically similar to Mycobacterium paratuberculosis, which causes Johne's disease in cattle. Like Crohn's disease, this disease is characterized by a transmural, chronically granulomatous, inflammatory reaction of the terminal ileum but also of the caecum, colon, and other areas of the bowel. It has been hypothesized that the clinical picture of Crohn's disease is the result of a host infection with Mycobacterium paratuberculosis, in all probability in the postnatal period, which becomes manifest following a latent period of a several years. This latent period may be compared with that observed in cattle, although the course of the disease is certainly not comparable. Animals with Johne's disease develop an ulcerative, wasting disease with enormous diarrhoea, and the organism can be isolated from both tissues and faeces. Infected animals nearly always die of the disease. These characteristics are not in agreement with Crohn's disease [6]. Seldenrijk et al. studied the T~cel]-mediated immune response to various Mycobacterium species in patients with chronic inflammatory bowel disease. They found no significant difference in response to these mycobacteria between the IBD patients and the control group. A relatively large portion of the control group showed a T cellmediated immune response to the mycobacteria, indicating t h a t the mycobacterial antigens are practically commensal [7]. One argument against an infectious aetiology is the observation t h a t health care workers, who come into frequent long-term contact with IBD patients and their partners, r u n no greater chance of developing the disease t h a n random individuals [4]. Moreover, antimycobacterial therapy is not generally effective against Crohn's disease. Environmental factors Nutritional factors. Some studies have demonstrated t h a t patients with Crohn's disease ingest diets containing large amounts of refined sugar and small amounts of vegetables and fibres. However, although such diets have been linked to cancer of the colon and rectum, their relationship with IBD is not clear [4]. Toothpaste has also been implicated as a possible cause of Crohn's disease [8], but this suggestion must be regarded as a fanciful hypothesis. Analogous to the suggested pathogenesis of peptic ulcer, Teahon has proposed t h a t the integrity of the mucosa of the small bowel is maintained by a balance between aggressive factors in the lumen (bile acids, pancreatic juices, bacteria, food components, etc.) and the mucosal defence factors, with the intercellular connections of contiguous enterocytes being the major factor t h a t limits macromolecular absorption. According to this theory, exacerbations of Crohn's disease are characterized by a serious disruption of the intercellular connections, so t h a t the mucosa is exposed to factors that induce inflammatory reactions. Elemental diet may modify the aggres-

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sive factors in the lumen to such an extent t h a t ations. The early laesions were of a focal nature restoration of the intestinal barrier function is and occurred in association with and contiguous possible. The greater importance of this barrier with normal vessels. This combination of characfunction in Crohn's disease is in line with obser- teristics suggested t h a t the observed vasculitis vations t h a t exacerbations are often preceded by was a primary process and did not occur seconexcessive use of alcohol, gastro-intestinal infec- dary to a general inflammatory reaction. The setion, and/or the use of nonsteroidal antiinflam- verity of this vascular damage seemed to be dimatory drugs (NSAIDs) [9]. rectly related to the severity of the i n t e s t i n a l Froese et al. reported on a 33-year-old woman disorder. who had undergone radical surgical excision in Of course, the question t h a t arises is, what meconnection with vaginal carcinoma at the age of chanism induces the thrombogenic injury in 11. When the patient was 19, the vagina was re- Crohn's disease? The authors suggested t h a t the constructed, for which purpose part of the sig- development of the fibrin deposit was mediated moid colon was used. Fourteen years later this by an interaction of lymphocytes and/or monowoman developed a vaginal haemorrhage, and a cytes with endothelial cells, which induced an inbiopsy of the neovagina revealed changes indica- crease in procoagulant activity, thus causing tive of ulcerative colitis. Within 2 weeks, the ischaemic injury to the intestinal wall. patient developed rectal haemorrhages, and a Mononuclear leukocytes have been found to atrectal biopsy also showed changes indicative of tach to the arterial endothelial tissue. It has also ulcerative colitis. The disease responded well to been demonstrated t h a t the granulomas characsulfasalazine. According to the authors, this case teristic of Crohn's disease are formed in the walls suggested t h a t the aetiology and pathogenesis of of blood vessels and that granulomatous vasculiulcerative colitis are more t h a n a local phenome- tis is a common pathological aspect of this disnon since the neovagina had not been exposed to ease. Since the interactions between leukocytes nutritional antigens for a period of 14 years. and endothelial cells are of fundamental imporAnother possibility was t h a t the neovagina had tance in the development of inflammatory reacalready been primed before the reconstruction. It tions, the authors studied the extent to which is also interesting t h a t sulfasalazine led to remis- drugs that are effective in the clinical t r e a t m e n t sion in this patient. It has been assumed t h a t the of Crohn's disease influence this leukocyte/endoefficacy of sulfasalazine is related to the local ac- thelial cell reaction. They noted t h a t corticostetion of free 5-amino-salicylic acid on the diseased roids inhibited the adhesion by decreasing the colon and t h a t the acetylated form or the ab- production of interleukin-1 (IL-1), t u m o u r necrosorbed 5-amino-salicylic acid is not involved. sis factor (TNF), gamma-interferon, leukotrieNevertheless, this patient's neovaginal colitis nes, and platelet-activating factor (PAF), and healed after t r e a t m e n t with oral sulfasalazine, t h a t drugs containing 5-amino-salicylic acid (5indicating a systemic effect of 5-amino-salicylic ASA) inhibited the production of leukotrienes. In acid [15]. addition, they found t h a t cyclosporin inhibited T Stress. Recent research has not been able to de- cell activation and the amplification of the immonstrate any relationship between stress or de- mune response. Since leukocyte/endothelial cell pression and the induction or exacerbation of interactions are a precondition for the developIBD [10]. merit of an inflammatory infiltrate, the inhibiSmoking. Relationships between ulcerative co- tion of leukocyte adhesion to the endothelial tis~ litis and non-smoking on the one hand, and be- sue is of great importance for the clinical effect of tween Crohn's disease and smoking on the other these drugs [16 17]. hand, have been reported m a n y times but are not clear [11 12]. Cope et al. found less colonic mucus Immunological abnormalities production in patients with ulcerative colitis There is no doubt t h a t the immune system t h a n in control subjects, but comparable mucus plays an important role in the inflammatory inproduction in ulcerative colitis patients who testinal disease process, although it is not yet smoked and controls [13 14]. clear whether the mucosal or systemic immunological abnormality is primary or secondary to Multifocal gastro-intestinal infarction the activity of the disease. A large n u m b e r of anWakefield et al. undertook a morphological tigens and microorganisms continuously pass study of portions of the small and large bowels the intestine together with chyme, and it is the t h a t had been resected in 15 patients with task of the local immune system to prevent contiCrohn's disease, and compared these with seg- nuous activation of inflammatory mechanisms. ments of intestine from a control group. They Immunoglobulin (Ig)A prevents antigens from demonstrated a pathogenetic series of events in passing the mucosa, so t h a t no complement forpatients with Crohn's disease: vascular damage, mation occurs and less inflammation is induced. focal arthritis, fibrin deposits, arterial occlusion, In the inflamed mucosa of patients with IBD, an mainly at the level of the tunica muscularis, fol- increased n u m b e r of plasma cells is present, in lowed by tissue infarction or neovascularisation. particular those t h a t produce IgG in ulcerative These findings were confined to those parts of the colitis and those t h a t produce IgM and IgG in intestine t h a t had been affected by Crohn's dis- Crohn's disease. However, the cells t h a t form ease and did not occur in the normal intestinal IgA constitute a majority. wall. The vascular damage appeared to have ocIncreased numbers of T cells have also been decurred early in the development of Crohn's lae- monstrated in the inflamed mucosa. Normal cosions and to have preceded the mucosal ulcer- lonic epithelium does not form HLA class-2 anti14(4A) 1992

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gens, except when there is a c t i v e inflammation as a result of IBD or other causes, such as infection. Thus, epithelial cells may start behaving as antigen-containing cells and cause further immune activation. It has been suggested t h a t an autoimmune disease may be involved in IBD in the form of a continuous immune response as a result of a specific immune regulatory abnormality [4 5].

matory effects by inhibiting the release of free arachidonic acid from membrane phospholipids through stimulation of the endogenous phospholipase-A2 inhibitor lipocortin [3 18]. The failure of specific cyclooxygenase inhibitors, such as indometacin and flurbiprofen, to induce statistically significant improvements in IBD indicates t h a t the lipoxygenase arm of the arachidonic acid cascade is more important t h a n the cyclooxygenase arm. 5-ASA is known to be a Eicosanoids weak cyclooxygenase inhibitor, but this cannot Eicosanoids are formed from arachidonic acid account for its therapeutic efficacy, in light of the via the so-called arachidonic acid cascade. This lack of effectiveness of NSAIDs in ulcerative colicascade is composed of two arms: the cyclooxyge- tis. nase and the lipoxygenase arm. Leukotriene B4 It has been further suggested t h a t sulfasala(LTB4) is formed via the 5-1ipoxygenase arm. zine stimulates the production of endogenous cyThis potent chemotactic substance attracts poly- toprotective prostaglandins, and t h a t 5-ASA and morphonuclear leukocytes and eosinophilic cells. sulfasalazine inhibit 5-1ipoxygenase and thus the It affects microvascular permeability, stimulates production of LTB4. However, the results of the the contraction of lymph vessels, and modulates various studies are not unambiguous. the inflammatory cell adhesion [18]. There is An alternative to the above hypothesis is that clear evidence that leukotrienes are involved in 5-ASA and sulfasalazine indirectly affect eicosathe potentiation of the inflammatory reaction in noid levels by acting as antioxidants or that they the colon. Sharon et al. demonstrated t h a t biop- scavage superoxide anion radicals and reduce sied mucosal tissue from patients with IBD con- the levels of the highly reactive oxygen metabverted 2.17% of exogenously presented arachido- olites formed during the oxidation of arachidonic nic acid into LTB4. In contrast, mucosal tissue acid [3 23]. In this regard it should be noted that biopsied from non-IBD patients converted only Verspaget et al. have demonstrated that patients 0.37% of arachidonic acid into LTB4. Mucosa with Crohn's disease and ulcerative colitis have from IBD patients also appeared to contain a reduced function of the neutrophil granulocytes, much higher level of LTB4 t h a n mucosa from the which appears to result from reduced superoxide control group [19]. anion production and reduced superoxide dismuNishida et al. demonstrated t h a t the inflamed tase concentrations. colonic mucosa of patients with ulcerative colitis Accumulation of the neutrophilic cells beside contained a higher lever of arachidonic acid t h a n the intestinal inflammation may nevertheless t h a t of healthy volunteers [20]. result in greater local production of toxic oxygen In order to compare the local release of arachi- radicals. These radicals may cause tissue injury donic acid metabolites, Lauritsen carried out an and ischaemia-like reactions if the local level of in vivo equilibrium dialysis of the rectum and de- protective superoxide dismutase is reduced. Lotermined the concentration of a n u m b e r of arm cal administration of superoxide dismutase may chidonic acid metabolites in the dialysate. The prevent this tissue injury [24 25]. study involved patients with IBD and with colitis In conclusion, it can be stated t h a t ulcerative due to Clostridium difficile infection. The concen- colitis differs markedly from Crohn's disease in a trations of prostaglandin (PG) E 2, PGF2_aipha, and number of aspects and t h a t both clinical entities thromboxane B2 were elevated in all groups of may be of a multifactorial nature. However, it is patients with colitis, as compared with healthy often difficult to distinguish cause and effect. volunteers. The concentration of 6-keto- The morphological study of Wakefield et al. has PGFI_alpha (the stable breakdown product of prostacyclin, PGI2) was not elevated. In the patients with ulcerative colitis, extreme increases in PGE2 and thromboxane B2 levels Pharmacotherapy of ulcerative colitis were observed. In addition, patients with ulcerative colitis exhibited considerably increased Haemorrhagic proctitis concentrations of leukotriene B4 relative to mesalazine patients with Crohn's colitis and Clostridium sulfasalazine difficile colitis [21]. - prednisolone In a rat model, Wallace et al. demonstrated t h a t inhibition of leukotriene synthesis mar- Mild to very severe disease kedly accelerated the healing of colitis [22]. sulfasalazine It is evident t h a t the eicosanoids, and in partimesalazine/olsalazine cular those formed via the 5-1ipoxygenase arm, - prednisolone play an important role in inflammatory bowel - azathioprine/6-mercaptopurine disease. This is especially true of LTB4, which has been shown both in vitro and in vivo to be in- Maintenance therapy volved in the pathogenesis of IBD. sulfasalazine The preparations used in the t r e a t m e n t of IBD mesalazine/olsalazine are known to exert an effect on eicosanoid pro- - azathioprine/6-mercaptopurine duction. Corticosteroids exert their antiinflamT a b l e

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Table

2

Pharmacotherapy of Crohn's disease Acute t r e a t m e n t - sulfasalazine - mesalazine/olsalazine - prednisolone - metronidazole - azathioprine/6-mercaptopurine Maintenance therapy - azathioprine/6-mercaptopurine

contributed greatly to clarifying the aetiology of Crohn's disease [16]. Treatment

of

IBD

P h a r m a c o t h e r a p e u t i c approaches to IBD [4 4349] are s u m m a r i z e d in Tables 1 and 2.

Sulfasalazine Since its introduction a h a l f century ago, sulfasalazine (Salazopyrine | has come to be considered the basis of t r e a t m e n t of ulcerative colitis and certain forms of Crohn's disease. Administered in a dosage of 4 g/day for 1 week and in a dosage of 2 g/day for 2 weeks, sulfasalazine produces symptomatic i m p r o v e m e n t and reduces disease activity in 80% of patients with mild ulcerative colitis, as compared with a 35% response r a t e a m o n g patients receiving placebo t r e a t m e n t . When used in a dosage of 4 to 6 g/day in mild to moderate ulcerative colitis, a response rate of 78% m a y be expected, as comp a r e d with 39% in patients being treated with placebo. Sulfasalazine is also effective in m a i n t a i n i n g remission in ulcerative colitis: 70% of patients t r e a t e d with 2 g/day are still in remission after one y e a r versus only 24% of patients t r e a t e d with placebo. Because bacterial cleavage in the colon is necessary for the release of 5-ASA, the probable active substance in sulfasalazine, the availability of 5-ASA in the small bowel is limited. This m a y account for the slight activity of oral sulfasalazine in Crohn's disease localized in the ileum. In mild to moderate Crohn's disease, sulfasalazine induces i m p r o v e m e n t in about two thirds of the patients, and should be regarded as p r i m a r y t h e r a p y in those whose disease is localized in the t e r m i n a l p a r t of the ileum and in the colon. The effect of the drug in patients with Crohn's disease in the small bowel and in Crohn's disease in remission is less predictable, however. A m inosalicy lates Olsalazine (Dipentum | is a prodrug consisting of two mesalazine molecules which are linked by an azo bond. As with sulfasalazine, mesalazine is released in the colon following bacterial cleavage of the azo compound. This similarity may, in cert a i n respects, be regarded as a benefit, in view of the experience with sulfasalazine. A drawback, however, is the development of diarrhoea in 14(4A) 1992

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about 17% of patients early in the course of treatment, which is related to a relatively high concentration of non-cleaved olsalazine [34 35]. The a d v a n t a g e of aminosalicylates over sulfasalazine is a more favourable profile of adverse reactions. Male patients who are infertile as a result of sulfasalazine-induced changes in sperm morphology or motility are candidates for switchover to an aminosalicylate. Research has shown t h a t oral and local mesalazine are as effective as sulfasalazine in the t r e a t m e n t of patients with mild to moderate active ulcerative colitis and in the prevention of relapse in patients with ulcerative colitis in remission [27 28]. C o m p a r a t i v e studies of the available mesalazine preparations (Asacol | Pentasa | and Salofalk | in the various forms of IBD are still lacking, although these p r e p a r a t i o n s h a v e been compared with regard to their local and systemic bioavailability [29], pharmacokinetic properties [30], and in vitro release profiles [31]. However, the clinical implications of the differences found in these studies r e m a i n to be established. At present, mesalazine and olsalazine offer no a d v a n t a g e s over sulfasalazine in patients who respond well to and tolerate sulfasalazine. Oral aminosalicylate p r e p a r a t i o n s are indicated in y o u n g m e n who wish to h a v e children and in patients who do not tolerate sulfasalazine well. Since mesalazine is only about 20% absorbed from the colon and has a m u c h more favourable side effect profile t h a n sulfasalazine, it can be administered both systemically and locally (by m e a n s of suppositories and enemas) in m u c h higher dosages t h a n are possible with sulfasalazine [26]. It can also be used in the t r e a t m e n t of more proximally situated disease t h a t cannot be reached with sulfasalazine. In addition, mesalazine suppositories and e n e m a s are highly effective for the t r e a t m e n t of refractory distal ulcerative colitis. In a recent l i t e r a t u r e review, J a n s s e n pointed out t h a t a prolonged (34-week) t r e a t m e n t course with mesalazine e n e m a s induced complete remission in 80% of subjects with ulcerative colitis who a p p a r e n t l y could not be t r e a t e d with conventional agents [32]. In a study of patients with self-sided ulcerative colitis in remission, D'Albasio et al. found comparable 12m o n t h recurrence r a t e s with oral sulfasalazine, 2 g/day (recurrence in 24% of cases), and mesalazine enemas, 4 g/day for the first seven days of the m o n t h (20% recurrence) [33]. A d i s a d v a n t a g e is t h a t patient compliance with a r e g i m e n of enem a s is less t h a n with oral therapy. (As H a n a u e r put it, " M a k e friends, not e n e m a s " [28].)

Corticosteroids Oral or p a r e n t e r a l corticosteroids (including prednisone, prednisolone, methylprednisolone, cortisone acetate and hydrocortisone) are indicated in the initial t r e a t m e n t of moderate to severe ulcerative colitis and Crohn's disease. The corticosteroid dose should be reduced after symptomatic mucosal remission h a s been achieved in patients with ulcerative colitis or when clinical i m p r o v e m e n t has occurred in p a t i e n t s with Crohn's disease. Corticosteroids h a v e not proven to be effective in m a i n t a i n i n g remission in ulcer279

ative colitis and Crohn's disease. If the disease regularly recurs, patients with ulcerative colitis should receive maintenance therapy with sulfasalazine, aminosalicy]ates or possibly an immunosuppressant, and patients with Crohn's disease should be treated with an immunosuppressant. Even after a patient with Crohn's disease has undergone intestinal resection, corticosteroids should not be used prophylactically.

Immunosuppressants Azathioprine (Imuran | and 6-mercaptopurine (Purinethol | are the two major immunosuppressant agents used in Crohn's disease and ulcerative colitis. Azathioprine is metabolized to 6-mercaptopurine. Both immunosuppressants have been demonstrated to be effective in 60% to 70% of patients with ulcerative colitis or Crohn's disease [36-41]. These immunosuppresant agents have been reported to cause such adverse effects as nausea, loss of hair, peripheral neuropathy, dose-related hepatotoxicity, and bone-marrow suppression. Pancreatitis, a hypersensitivity reaction, occurs in 3% to 15% of the patients and appears to be reversible following discontinuation of therapy. The greatest risk, however, is carcinogenicity. Both 6-mercaptopurine and azathioprine have been demonstrated to cause reversible chromosomal changes in h u m a n beings, although an increase in neoplasms has thus far not been demonstrated in non-transplant patients. In patients with Crohn's disease, 6-mercaptopurine or azathioprine m a y be used in the following circumstances: - in patients with chronically active disease who do not respond to sulfasalazine, corticosteroids or metronidazole; - in patients who experience severe side-effects of steroid therapy, such as hypertension, osteoporosis and fractures, diabetes, or psychosis; - in patients who have been continuously using prednisone in doses higher t h a n 15 rag/day for six months or longer; - in patients with chronic fistulas, such as perianal, rectovaginal, abdominal wall, largebowel, and ileovesical fistulas; - in patients who are eligible for extensive surgery such as total colectomy or major smallbowel resection; - to maintain remission, particularly in patients with very extensive disease or disease that has been chronically active for many years. In ulcerative colitis, one should be somewhat more reluctant to use immunosuppressive agents because, in principle, surgery is curative. When these agents are used in ulcerative colitis, they should be prescribed for two to three years following the induction of remission, in order to maintain the remission that occurs in 70% of patients [42]. Indications for immunosuppressant therapy include: - chronic disorders t h a t do not respond to corticosteroids and sulfasalazine; - patients who experience severe adverse reactions to corticosteroids (see above); - patients with proctosigmoiditis t h a t does not 280

respond to conventional oral and local therapy (sulfasalazine, mesalazine compounds); - patients with Continuously active left-sided or total colitis who have not had the disease long enough (more t h a n 10 years) to run a greater risk of developing colonic carcinoma.

Metronidazole and other antimicrobials The value of metronidazole in the t r e a t m e n t of ulcerative colitis has not been demonstrated. In Crohn's disease, on the other hand, metronidazole, 10 to 20 m g . k g 1.d-1, is effective in the t r e a t m e n t of mild to moderate exacerbations, particularly of perianal disease. Continuation of therapy may be necessary to prevent relapse, while the patient should be carefully monitored for signs and symptoms of peripheral neuropathy, which develops in up to one half of patients taking metronidazole. In a double-blind placebo-controlled trial conducted in 84 patients with acute relapsing ulcerative colitis, Burke et al. achieved complete symptomatic remission in 74% of patients treated with oral tobramycin as an adjunct to steroid therapy, as compared with a 43% remission rate in the placebo group [43]. Gradon reported a dramatic response to trimethoprim-sulfamethoxazole in a patient with idiopathic Crohn's colitis t h a t did not respond to sulfasalazine [44]. New

pharmacotherapeutic

developments

Recent developments in the pharmacotherapy of IBD are summarized in Table 3.

Aminosalicylates It is interesting to note that 4-amino-salicylic acid (PAS) has also been used locally in the form of enemas. 2 g Of 4-amino-salicylic acid administered by enema has appeared to be a good alternative to mesalazine enema therapy [47 51]. In addition to olsalazine, the azo compounds balsalazide and ipsalazide have been developed, in which the mesalazine molecule is bound to a benzoylalanine or benzoylglycine group, respectively. However, little or no clinical research has been conducted using these compounds in IBD [50]. Corticosteroids As with oral administration of corticosteroids, rectal administration may cause suppression of

Table

3

Agents in the pipeline for treatment inflammatory bowel disease (IBD)

of

Aminosalicylates Corticosteroids (for new preparations, see Table 4) Immunosuppressive drugs Lipoxygenase inhibitors (see Table 5) Fish oil Others (bismuth, hydroxychloroquine, sodium cromoglycate, methotrexate)

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the hypothalamus-hypophysis-adrenal axis. The T a b l e 4 severity of side-effects and the toxicity of rectally New corticosteroid preparations for the treatment administered corticosteroids depend on the total of inflammatory bowel disease (IBD) dose administered, the duration of t r e a t m e n t , the degree to which the active form of the steroid Beclomethasone diproprionate is absorbed, and the r a t e at which the prepar- Prednisolone metasulfobenzoate (PMSB) ation is metabolized to inactive compounds. Al- Tixocortol pivalate though short-term t r e a t m e n t is r a r e l y associated Fluticasone propionate with severe side-effects, prolonged t r e a t m e n t is Budesonide accompanied by the s a m e side-effects seen with chronic systemic corticosteroid t r e a t m e n t . These problems h a v e stimulated a search for new preparations t h a t offer the s a m e a n t i i n f l a m m a t o r y a dosage of 250 m g per 100 ml of enema, tixocoractivity and clinical effectiveness as conven- tol pivalate is as effective as hydrocortisone, tional corticosteroids but lack the associated 100 mg in a 60 or 100 ml enema, in patients with side-effects. left-sided ulcerative colitis [51 54]. In the NetherThe limitation of the effect of these newly deve- lands tixocortol pivalate e n e m a is available as loped corticosteroids on the intestinal mucosa is Rectovalone | closely related to the m e t a b o l i s m of these prep- " Fluticasone propionate is a new corticosteroid arations. The new preparations undergo a high which is locally twice as potent as beclomethadegree of first-pass m e t a b o l i s m in the circulation sone dipropionate. It undergoes first-pass metabby erythrocytes and in the liver, resulting in me- olism in the liver, where it is converted into tabolites with little or no biological activity. metabolites with little activity. Absorption from P r e p a r a t i o n s t h a t fall into this category include the intestine is less t h a n 50%, which is likely to beclomethasone dipropionate, prednisolone me- reflect the drug's low w a t e r solubility, which tasulfobenzoate, tixocortol pivalate, budesonide, largely limits its u p t a k e via the intestinal and fluticasone propionate (Table 4) [51-54]. mucosa. In a pilot study on the use of 20 m g of Beclomethasone dipropionate e n e m a s have fluticasone propionate orally for t h r e e weeks in been compared with prednisolone phosphate and the t r e a t m e n t of mild to moderately active b e t a m e t h a s o n e phosphate enemas in patients Crohn's disease, Carpani de K a s k i et al. reported with distal ulcerative colitis. The effectiveness of a significant drop in the Crohn's Disease beclomethasone dipropionate is similar to t h a t of Activity Index (CDAI), no effect on p l a s m a cortithe other corticosteroids. In doses up to 4 mg/d sol levels, and no severe side-effects [55]. orally or via inhalation, beclomethasone dipropiBudesonide. The best documented 'new' cortionate has no effect on the h y p o t h a l a m u s costeroid in the t r e a t m e n t of IBD is budesonide. h y p o p h y s i s - a d r e n a l axis, probably because the Locally budesonide is twice as potent as beclomeabsorbed drug is converted into pharmacologi- thasone dipropionate, which m e a n s t h a t it is cally less active or inactive metabolites. Mulder about 200 and 15 times as potent as hydrocortihas reported t h a t a d m i n i s t r a t i o n of beclometha- sone and prednisolone , respectively. In consone dipropionate in doses up to 6 m g by e n e m a trolled studies with prednisolone enemas, budepermits reduction and eventual discontinuation sonide appeared to be superior to prednisolone of oral and local prednisone t h e r a p y in patients according to all p a r a m e t e r s measured. Endowith left-sided ulcerative colitis [54]. genous cortisol concentrations were not signifiH a l p e r n et al. found t h a t 0.5 m g beclometha- cantly affected by budesonide in the dosages sone e n e m a s were as effective as 5 m g beta- used. Budesonide is 100 t i m e s as w a t e r soluble as m e t h a s o n e e n e m a s given for 28 days in beclomethasone dipropionate and fluticasone 32 patients with distal ulcerative colitis. In con- propionate. This g r e a t e r solubility enhances the t r a s t to b e t a m e t h a s o n e , beclomethasone dipro- u p t a k e of the drug in the intestinal wall. Budesopionate did not cause steroid-related side-effects nide is well-absorbed; its bioavailability of bude[55]. Beclomethasone dipropionate tablets are sonide is a p p r o x i m a t e l y 10% following oral currently being developed for oral t r e a t m e n t of administration and a p p r o x i m a t e l y 15% followIBD. ing rectal administration. In the liver it is Prednisolone metasulfobenzoate (PMSB). When metabolized to metabolites t h a t are at least administered as an enema, this prednisolone 100 times less active t h a n budesonide itself [52]. compound is absorbed to a lesser extent t h a n In a study of 64 patients with ulcerative colitis, prednisolone phosphate, which results in lower Danielsson et al. observed endoscopic healing afp l a s m a prednisolone levels. Sulfa-like side reac- ter four weeks in 52% of patients who were tions of PMSB h a v e been repored. Curiously t r e a t e d with 2 m g of budesonide in a 100 ml enough, w h e n a d m i n i s t e r e d as a foam, PMSB ap- enema, as compared with 24% of patients who repears to be absorbed as well as prednisolone ceived 31.25 mg of prednisolone phosphate in phosphate [38 47]. 100 ml once daily. Endogenous cortisol levels Tixocortol pivalate is a non-glucocorticoid, non- were not affected in the budesonide group, in conmineralocorticoid derivative of cortisol. Follow- t r a s t to the significant decreases s e e n in patients ing absorption from the rectum, it undergoes ra- in the prednisolone group [57]. pid first-pass m e t a b o l i s m by the erythrocytes L a m e r s et al. compared the efficacy and sideand the liver, so t h a t the product does not show effects of 2 m g of budesonide in a 110 ml e n e m a systemic activity. Consequently, tixocortol piva- with those of 4 g of mesalazine in a 60 ml e n e m a late has no effect on the p l a s m a cortisol level. In once daily in patients with proctitis and procto14(4A) 1992

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sigmoiditis. After four weeks of treatment, 11 of the 32 patients from the budesonide group and 11 of the 30 patients from the mesalazine group were endoscopically cured. Endoscopic improvement was seen in a total of 23 patients from the budesonide group and in 26 patients from the mesalazine group. The authors concluded that budesonide enemas were as effective as highdose mesalazine enemas in the t r e a t m e n t of proctitis or proctosigmoiditis [58], but had a more favourable side-effect profile. In an open study of 72 patients with proctitis, Tarpila et al. found t h a t 2 mg of budesonide per 100 ml of enema was as effective as a foam containing 125 mg of hydrocortisone per 5 ml. Unlike the hydrocortisone foam, budesonide did not affect plasma cortisol levels [59]. The budesonide enema t h a t has been registered in some countries under the name of Entocort | consists of two components: a tablet containing 2.3 mg of budesonide and 115 ml of solvent. The enema is prepared by dissolving the tablet before administration and by mixing it with the enema liquid. In addition to the enema formulation, two sustained-release budesonide capsules are presently undergoing clinical study. With one preparation, the drug is released in the ileum and with the other, it is released in the colon. The release of budesonide is pH-dependent and time-dependent. LSfberg et al. studied the effects of oral budesonide capsules, 9 mg/day for 12 weeks, followed by 6 mg/d for 6 weeks and t h e n by 3 mg/day for another 6 weeks, in 21 patients with active Crohn's disease localised in the distal ileum and/or the ascending colon. Surgery was being considered in these patients, who had failed to respond adequately to conventional therapy. Budesonide appeared to be effective, and the average plasma cortisol levels remained within the normal range throughout the study [60]. In a study of 17 patients with refractory moderate to severe Crohn's disease localized in the terminal ileum and/or the proximal colon, Wolman et al. found t h a t oral budesonide significantly decreased the CDAI. In 9 patients the improvement was sufficient to eliminate the need for surgery [61]. On the basis of the studies described above, it may be concluded t h a t budesonide and tixocortol pivalate are promising new agents in IBD. Immunosuppressants

sporin-treated patients but in only 32% of placebo-treated patients. The CDAI improved significantly during cyclosporin treatment. Following reduction of the ciclosporin dosage for a second 3-month study period, the proportion of ciclosporin-treated patients who showed improvement dropped to 38%, as compared with 15% in the placebo group. Subsequent follow-up revealed that, 12 months after the start of treatment, 19% of patients in the cyclosporin group had improved, as compared with 9% of the patients in the placebo group. This translated into a therapeutic benefit of 10% (confidence interval, - 6 to 26%). The authors concluded t h a t short-term t r e a t m e n t with ciclosporin does not result in improvement of active chronic Crohn's disease over the long t e r m [62 63]. Lichtiger et al. administered intravenous corticosteroids and intravenous ciclosporin, 4 mg. kg -1.d -1 to 15 patients with severe ulcerative colitis, 14 of whom had not responded to at least 10 days of t r e a t m e n t with intravenous steroids alone. Eleven of the 15 patients (73%) improved sufficiently to eliminate the need for colectomy. The average response time was 5.8 days. Patients who had responded well were t h e n treated with cyclosporin, 6 to 8 m g - k g - ~ . d -~ orally, for 6 months. In 6 of the 11 patients the corticosteroid dose could be reduced and eventually stopped. These patients remained in clinical and endoscopical remission for 5 to 18 months following discontinuation of ciclosporin. In three of the 11 patients, the corticosteroid dose could be reduced. These patients were still in remission 5 months after discontinuation of cyclosporin. One patient relapsed after five months of oral ciclosporin therapy and underwent colectomy. The last of the 11 patients who had responded well to intravenous therapy became worse during oral t r e a t m e n t with ciclosporin period, was switched to mercaptopurine treatment, and went into remission. None of the patients needed to be withdrawn from the study as a result of adverse reactions. Mild side-effects occurred in 9 patients, and included hypertrichosis (5 patients), mild paresthesias (6), tremor (5) and hyperplasia of the gingiva (2). The authors concluded that this form of ciclosporin therapy is a useful new t r e a t m e n t in ulcerative colitis [64]. F u r t h e r clinical controlled studies are required, however, to determine the definitive position of ciclosporin in the m a n a g e m e n t of IBD. Until more efficacy and toxicity data are available, cyclosporin cannot be recommended for routine t r e a t m e n t of ulcerative colitis or Crohn's disease.

Ciclosporin is an immunosuppressant which is used for the prevention and t r e a t m e n t of rejection reactions in patients who have undergone organ or bone-marrow transplantation. The drug probably inhibits the synthesis or release of Lipoxygenase inhibitors It has been demonstrated t h a t the capacity of interleukin-2, which reduces helper T cell function. This inhibits the formation of cytotoxic the colonic mucosa to synthesize ]eukotrienes is greater in patients with IBD t h a n in normal sublymphocytes which cause tissue injury. Ciclosporin has also been used in IBD [48]. In jects. Elevated leukotriene levels have been dea study of 71 patients with active Crohn's disease monstrated in colonic tissue from patients with t h a t had not responded adequately to cortico- IBD. LTB4 is a well-known chemotactic and prosteroids, Brynskov et al. compared the effects of inflammatory agent. Sulfazalazine and mesalaciclosporin, 5 to 7.5 m g . k g - l . d -~ orally, with zine have been demonstrated to inhibit leukoplacebo. At the end of the 3-month t r e a t m e n t per- triene biosynthesis. The production of leukotrienes as well as of cyiod, improvement had occurred in 59% of ciclo282

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Table 5 Lipoxygenase inhibitors Arachidonic acid-related substances Antioxidants Phenidone and derivatives Hydroxy amino acid derivatives Activation inhibitors

clooxygenase products can be blocked by the inhibition of phospholipase A2, which prevents the release of arachidonic acid from phospholipids. In this way, corticosteroids influence both the lipoxygenase arm and the cyclo-oxygenase arm of the arachidonic acid cascade. Through specific inhibition of 5-1ipoxygenase (Table 5), the biosynthesis of all leukotrienes is inhibited. Unlike the inhibition of phospholipase A2, the cyclooxygenase arm of the arachidonic acid cascade remains intact when 5-1ipoxygenase is inhibited. Theoretically it is also possible to selectively inhibit the production of LTB4 further in the process of leukotriene synthesis. However, this may lead to an increase in the production of other leukotrienes. Research has also been done on substances t h a t inhibit both 5-1ipoxygenase and cyclo-oxygenase: the so-called dual inhibitors. Various types of 5-1ipoxygenase inhibitors can be distinguished (Table 5). Arachidonic acid-related substances. This term refers to substances t h a t are so similar to arachidonic acid t h a t 5-1ipoxygenase cannot distinguish between them. One of these compounds is 5,8,11,14-eicosatetraynoic acid (ETYA), in which the double bonds of arachidonic acid have been replaced by triple bonds. ETYA competitively inhibits 5-1ipoxygenase. Antioxidants. The oxidative metabolism of arachidonic acid by 5-1ipoxygenase can be influenced by numerous antioxidants. These inhibitors of 5-1ipoxygenase act either by destroying hydroperoxides needed for enzyme activation, or by scavenging ferric ions, which catalyse the 5lipoxygenase oxidation of arachidonic acid. Wellknown antioxidants are alpha-tocopherol (vitamin E) and nafazatrom. Phenidone and derivatives. Phenidone, which is used as a developer in photography, was one of first compounds demonstrated to inhibit leukotriene biosynthesis. In fact, phenidone inhibits both 5-1ipoxygenase and cyclooxygenase. Various compounds have been derived from phenidone, the best known of which is BW-755C, likewise a dual inhibitor. Hydroxy amino acid derivatives. Hydroxy amino acids are excellent binders of the ferric ion, which catalyses the 5-1ipoxygenase oxidation of arachidonic acid. The best known hydroxy amino acid derivative is Zileuton (A-64077). Zileuton is a selective inhibitor of 5-1ipoxygenase in vitro and a potent inhibitor of leukotriene biosynthesis in vivo. Activation inhibitors. During leukotriene biosynthesis, translocation of 5-1ipoxygenase from the cytosol to the cell membrane takes place. This translocation appears to be an important 14(4A) 1992

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step in the activation of 5-1ipoxygenase. Activation inhibitors can prevent and undo the membrane translocation of 5-1ipoxygenase. Other types of lipoxygenase inhibitors appear not to influence this translocation process. The best known activation inhibitor is MK-886 (L-663, 536). This substance has been shown to be active in animal models and has been studied in humans. However, the development of this substance has been discontinued because its effectiveness left something to be desired [65]. Clinical studies. The 5-1ipoxygenase inhibitor in the most advanced stage of development is Zileuton (Figure 1). This drug has been shown to be a potent, selective, and orally effective inhibitor of 5-1ipoxygenase in in vitro and animal pharmacological studies [68-70]. Zileuton is readily absorbed and has an elimination half-life of 3h, independent of the administered dose. At a dosage of 800 mg b.i.d, no accumulation occurred. From the relatively short half-life and from blood levels measured at a dose of 600 mg t.i.d. or q.i.d., it appears t h a t q.i.d dosing is necessary to achieve continuous inhibition of LTB4 production [72]. Staerk Laursen et al. have determined the leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) concentrations in rectal dialysis liquid before and after oral administration of 800 mg of Zileuton in 10 patients with active ulcerative colitis. The average LTB4 concentration decreased significantly, in contrast to the PGE 2 concentration. After 28 h, the LTB4 concentration had returned to the initial level [66]. The same authors compared the effects of oral Zileuton, 800 mg b.i.d, for 28 days, in 11 patients with active ulcerative colitis with the effects of placebo in 13 patients. There appeared to be a trend toward improvement among patients in the Zileuton group although the difference did not reach statistical significance because of the small number of patients involved [67]. In a 28-day study of Zileuton, 800 mg q.d., in mild to moderately active ulcerative colitis, Collawn et al. observed histological improvement was observed in 4 of 11 patients and no change in the remaining 7 patients [68]. SC-45662, a 5-1ipoxygenase inhibitor, and SC41930, an LTB4 receptor antagonist, appear to inhibit LTB4 release from fresh rectal mucosa biopsies more markedly t h a n 5-ASA. BW-A4C, a 5-1ipoxygenase inhibitor, also appears to inhibit LTB4 production in mucosa biopsies from ulcerative colitis patients [3]. Although it will certainly take some years before 5-1ipoxygenase inhibitors are available as drugs, the expectations for these agents are certainly positive. In summary, the use of lipoxygenase inhibitors is based on fundamental (patho)physiological research which has demonstrated elevated leukotriene B4 concentrations in the colon of IBD patients. Establishment of the efficacy of these drugs in the t r e a t m e n t of IBD will require further controlled clinical studies. Fish oil. Eicosapentanoic acid and docosahexanoic acid are important u n s a t u r a t e d components of fish oil. Like arachidonic acid, eicosapentanoic 283

acid is a substrate for 5-1ipoxygenase, from which leukotriene B5 is formed. However, leukotriene B5 is a markedly less potent chemotactic agent for neutrophilic cells t h a n LTB4. The difference is at least a factor of 30 when induction of calcium mobilisation, chemokinesis, and the degranulation and aggregation of polymorphonuclear cells are considered. It is thus interesting to study whether dietary fish oil is useful for the t r e a t m e n t of ulcerative colitis and Crohn's disease. Small open studies have suggested that significant symptomatic and histological improvement follows the inclusion of fish oil, 3 to 4 g/day for 12 weeks, in the diet of ulcerative colitis patients. Fish oil does not appear to change the clinical activity of Crohn's disease, however [3]. Pajares et al. studied the effect of dietary fish content on clinical course in 38 patients with Crohn's disease in remission. Half the patients were given a diet rich in fish and the other half were free to choose their own diet. Neither group took any drugs. After 2 years, relapses had occurred in only one fifth of the fish eaters but in more t h a n half of patients in the free diet group [73]. F u r t h e r study is required to determine the value of fish oil in the t r e a t m e n t of IBD.

Other drugs Sucralfate. In an open study involving patients with distal ulcerative colitis, a 10% sucralfate enema appeared to be effective. However, in a controlled study, only 28% of patients treated with sucralfate went into remission, as compared with 71% of patients treated with prednisolone enemas. Likewise, it appears from other studies t h a t sucralfate enemas are comparable with placebo [3 51]. Bismuth compounds. According to a report from Srivastava et al., t r e a t m e n t with bismuth subcitrate enemas for 4 weeks led to symptomatic, endoscopic and histological improvement in nine of 11 patients with active proctitis or proctosigmoiditis [74]. In a study of ulcerative colitis t h a t had not responded adequately to sulfasalazine, mesalazine, and corticosteroid therapy, Ryder et al. found that bismuth salicylate enemas produced symptomatic improvement in 9 of 15 patients, endoscopic improvement in 11, and complete remission in 6. The corticosteroid dose could be reduced in 10 patients and completely discontinued in 5. Weekly prophylactic treatmerit with a bismuth salicylate enema was continued in a number of patients who had achieved remission [75]. Free radical scavengers. Free oxygen radicals, which are formed during the inflammatory process, can be cytotoxic. One of the supposed mechanisms of action of mesalazine is the scavenging of these free radicals. Superoxide dismutase, a well-known free radical scavenger, is also being used successfully in open studies in patients with Crohn's disease and ulcerative colitis. However, further controlled clinical studies are necessary to assess the value of superoxide dismutase in IBD. D-Penicillamine, a nonenzymatic radical scavenger, has also been used successfully in a 284

number of patients with Crohn's disease [51]. (Hydroxy)chloroquine. (Hydroxy)chloroquine has antiinfiammatory and immunoregulatory properties, and chloroquine has been used in open clinical trials of IBD. After 8 weeks of treatment, clinical and endoscopic improvement was seen in 8 of 10 patients with ulcerative colitis but in none of the patients with Crohn's disease. Hydroxychloroquine is currently being studied clinically in ulcerative colitis [51]. Sodium cromoglycate. In patients with ulcerative colitis the number of mast cells in the intestinal mucosa appears to be increased, relative to patients with Crohn's disease and in non-IBD patients [76]. For this reason, sodium cromoglycate has been tried in patients with ulcerative colitis. Orally the drug appears to have no effect. A 600-mg cromoglycate enema, however, was comparable in efficacy to a 20-mg prednisolone enema in a 9-week trial involving 70 patients with distal ulcerative colitis and proctitis [77]. Methotrexate. In a study by Kozarek et al., methotrexate, 25 mg intramuscularly once a week for 12 weeks, produced objective improvement in 11 of 14 patients with refractory Crohn's disease and in 5 of 7 patients with refractory ulcerative colitis. Endoscopic remission was seen in 5 of the 7 patients with Crohn's disease and colitis but in none of the patients with ulcerative colitis [78]. These authors tried the same methotrexate regimen in 14 patients with Crohn's disease and 6 patients with ulcerative colitis t h a t had not responded to six months of t r e a t m e n t with 6mercaptopurine or azathioprine. The 16 patients who responded well to intramuscular methotrexate were continued on t r e a t m e n t with oral methotrexate, 15 mg/week. Of 12 evaluable patients, 8 (67%) remained in remission for an average of 71.5 weeks. Side-effects included nausea, accelerated alopecia, leukopenia, and mild elevation of ASAT/alkaline phosphatase [79]. F u r t h e r controlled clinical study is necessary to assess the value of methotrexate in the treatment of IBD. Miscellaneous reports. Finally, it may be mentioned that: -lidocaine rectal gel, 800 mg/day for 3 to 8 weeks, has appeared to be effective in a majority of patients studied with ulcerative proctitis and proctosigmoiditis [80]; -immunoglobulin, 400 m g - k g - l . d -1 intravenously for five days, appeared to be effective in 9 of 13 patients with ulcerative colitis [81]; - Gaffney reported on a patient with ulcerative colitis who improved markedly after treatmerit with intravenous heparin for deep venous thrombosis. 2 Other patients who had not responded to sulfasalazine, alone or in combination with prednisolone, also improved following t r e a t m e n t with intravenous and subcutaneous heparin [82]; - transdermal nicotine, 15 mg on day I followed by 30 mg for 4 weeks and then by placebo for 4 weeks, produced symptomatic improvement in 12 of 16 patients with ulcerative colitis, endoscopic improvement in 12, and histological improvement in 10 patients. It should be noted

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t h a t t h e p a t i e n t s ' u s u a l m e d i c a t i o n s (prednisolone, m e s a l a z i n e , etc.) w e r e c o n t i n u e d d u r i n g t h i s s t u d y [83]. (This s t u d y a g a i n r a i s e s t h e q u e s t i o n of w h e t h e r s m o k i n g protects a g a i n s t u l c e r a t i v e colitis, a f t e r all.)

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Conclusion In the near future, the pharmacotherapeutic a r s e n a l for t h e t r e a t m e n t of IBD will be e x t e n d e d w i t h more r e c t a l l y a p p l i c a b l e corticosteriods, w h i c h h a v e l i t t l e or no s y s t e m i c effect. Over t h e s l i g h t l y l o n g e r t e r m , t h e s e p r e p a r a t i o n s will also become a v a i l a b l e as oral f o r m u l a t i o n s . F u r t h e r d o w n t h e road, we c a n expect t h e i n t r o d u c t i o n of l i p o x y g e n a s e i n h i b i t o r s w h i c h selectively reduce t h e l e u k o t r i e n e B4 c o n c e n t r a t i o n . T h e effectiven e s s of ciclosporin, fish oil, a n d b i s m u t h e n e m a s will r e q u i r e c o n f i r m a t i o n i n f u r t h e r c o n t r o l l e d c l i n i c a l studies.

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Acknowledgements T h e a u t h o r t h a n k s Mrs. M.E. B o v e n h o f f a n d G. d e n H a r t o g , Ph.D., g a s t r o e n t e r o l o g i s t , for critically r e a d i n g t h e m a n u s c r i p t , Mrs. H.J. Zegersde Schipper a n d Mrs. P.S. H a r i n c k for p r e p a r i n g t h e m a n u s c r i p t , a n d F r e d e r i c k J.A. M o s t e r t for the English translation.

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P h a r m a c e u t i s c h Weekblad Scientific edition

14(4A) 1992