overview: new directions in inflammatory bowel disease therapy

Anti-inflammatories efc. 61 5

Overview

New Directions in Inflammatory Bowel Disease Therapy

Brian Carlson and SNS Murthy Krancer Center for Inflammatory Bowel Disease Research, Division of Gastroenterology,

Department of Medicine, Hahnemann University, Philadelphia, PA 19102, USA Correspondence: SNS Murthy

Introduction Inflammatory bowel disease (IBD) is composed of Crohn’s disease and ulcerative colitis. Its etiology is unknown and therefore curative therapies are lacking. Empirical therapeutics dominate the pharmacopoeia of IBD, steroids and sulfasalazine representing the mainstay of therapy. Current research is directed towards the elucidation of the inflammatory response in IBD. The demonstration of increased synthesis of LTB4 from mucosa of patients with IBD has solidified interest in the role of inflammatory mediators in IBD [ 11. Several animal models of dammation provide suitable if not entirely representative frameworks on which to test the effect of mediator antagonists [2-51. The present paper will present an overview of future therapeutic agents in IBD based on these models of dammation and human trials. Special reference will be made to leukotriene and eicosanoid inhibitors, immunomodulators, cytokine inhibitors, anti-oxidants and free radical scavengers.

Sulfasalazine and its congeners Sulfasalazine has demonstrated efficacy in the treatment of active IBD and the maintenance of remission in ulcerative colitis [6-81. The mechanism of action of sulfasalazine and its active ingredient 5-aminosalicyclic acid (5-ASA) includes cyclooxygenase [9] and lipoxygenase [ 10,111 inhibition, decreased free radical information [ 121 and active free radical scavenging properties [13]. The therapeutically active portion of sulfasalazine is 5-ASA [14] and the toxicity of sulfasalazine resides in the sulfapyridine moiety [15,16]. The identification of the active portion of the sulfasalazine molecule has prompted the search for less toxic therapeutic entities. These include topical salicylate enemas and newer oral agents that lack sulfapyridine. Trials with topical 5-ASA enemas have demonstrated clinical remission or improvement in 75-90% of patients [ 17-19]. CASA enemas are also efficacious and appear to be more stable than 5-ASA in saline solution (20,211. Oral agents include delayed release forms, molecules of 5-ASA azo-bonded to itself (olsalazine) [22), and azo-bonded molecules of 5-ASA to an inert vehicle (balsalazide) [23,24].

0 Current Patents Ltd ISSN 0962-2594

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616 Overview - Inflammatory Bowel Disease Therapy - Carlson, Murthy

Steroids ~~

Steroids remain the most accessible and effective treatment for acute exacerbations of IBD. Stabilisation of cellular membranes and inhibition of phospholipase A2 (PLA2), perhaps via a second messenger, lipocortin [25], have been postulated as its mode of action. The latter represents an impetus for the development of other PLA2 inhibitors. Newer typical steroid agents include beclomethasone dipropionate [26], budesonide [27], and tixocortal pivalate [28], a derivative of cortisol and fluticasone propionate [29]. These topical steroids are tar- geted to produce high intrinsic glucocorticoid activity, rapid absorption and inactivation, and minimal local bi otransforma tion.

Specific PLA2 inhibitors include pBPB, ellagic acid, aristocholic acid, gossypol, and luf- fariellolide [30]. SmithKline Beecham Pharmaceuticals has developed a unique phosphonate- phospholipid analogue [3 11, designed as a transition state inhibitor. This compound has been shown to inhibit human PLA2 and may find utility in IBD.

Allergan, Inc. has developed AGN 190383 a 2(SH)-furanose ring analogue of manoalide which has been shown to inhibit PMA-induced mouse ear oedema [32]. It is also a potent inhibitor of bee venom PLA2 and arachidonic acid release fiom stimulated neutrophils suggesting a potentially therapeutic role in IBD.

Eicosanoid inhibitors Using a rectal dialysis procedure first demonstrated by Lauritsen and colleagues [33], Zipser, et al. have demonstrated that there is a quantitative relationship between severity of colon aammation and production of the arachidonic acid metabolites PGE2, LTB4, and LTC4 in patients with IBD [3]. Supporting evidence for the role of LTB4 in IBD has been provided via animal models [2-51.

The increased levels of cyclooxygenase and lipoxygenase products in active IBD suggest a therapeutic role for combined cyclooxygenasellipoxygenase (CO/S-LO) inhibition. Cyclooxy- genase inhibition alone has proven detrimental to colonic mucosa and supports a cytoprotec- tive role for certain members of the prostaglandin class [34-361. A prototype of the combined CO/S-LO inhibitor is BW755C [37]. This agent has been shown to significantly inhibit the increased fonnation of 6-Keto-PGFl. and LTB4 normally produced by trinitrobenzenesulphonic acid (TNBS)-induced colonic inflammation in rats. However, it did not significantly reduce colonic damage in the same model [38]. Additional putative C0/5-L0 inhibitors are tenidap and tolfenamic acid. Both agents have been shown to inhibit the cyclooxygenase product, TXB2, and the 5-lipoxygenase product, LTB4, in plasma-free leukocyte suspension. However, in human blood and after oral administration to rabbits, 5-LO inhibition could not be demonstrated [39]. This suggests significant decreases in lipoxygenase inhibitory activity in plasma protein milieus and limits these agents to CO inhibition alone.

5-Li poxygenase inhibitors Supporting evidence for the role of LTB4 in IBD has been provided by animal models [2-51. LTB4 causes neutrophil chemotaxis, adherence to endothelium, degranulation and oxidative burst [40]. Remission of inflammation associated with a decrease in LTB4 production supports a therapeutic role for 5-lipoxygenase inhibition in IBD [4,5].

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Anti-inflammatories etc. 61 7

Specific lipoxygenase inhibition should decrease the levels of the potent pro-inflammatory LTB4. Both animal studies and human studies support this hypothesis [30,41,42].

One of the better studied compounds is A64077 (Zileuton, Abbott Laboratories). In a rat anaphylaxis model this orally active 5-LO inhibitor decreased LTB4 biosynthesis with an ED50 of 6 mgkg. Histamine and thromboxane levels were unaffected indicating enzyme specificity [43]. Phase 1 studies in human volunteers have borne out this selective decrease in LTB4 biosynthesis [a]. In a double-blind, randomised trial of A64077 vs placebo in 11 patients with ulcerative colitis, there was a trend towards improvement measured via sigmoidoscopic, symptom, biopsy scores and global evaluation [45]. Equilibrium dialysis measurement of LT34 and PGE2 has been performed on ten patients with ulcerative colitis before and after oral dosing with A64077. Significant decreases in LTB4 levels were noted at 4-8 hours after dosing and return to baseline at 24 hours. PGE2 levels were also increased at the 4-8 hour post dosing time interval [46]. These studies suggest the need for further human studies to codirm the efficacy of A64077 in IBD.

WY-50,295 (Tromethamine, Wyeth-Ayerst Research) has been shown to reversibly inhibit LTB4 production with an IC50 of lpM in calcium ionophore A23187-stimulated human leuko- cytes [30].

L65 1,392, a phenothiazinone derivative, specifically inhibits 5-lipoxygenase without affecting cyclooxygenase or 12-, 15-lipoxygenase activity. Amelioration of bronchoconstrictive disease in animal models has been demonstrated via its 5-lipoxygenase inhibition [47]. Significant inhibition of leukotriene biosynthesis by rat gastric mucosa has also been demonstrated [48]. In the TNBS model of rat colitis daily intracolonic administration of L651,392 decreased colonic LTB4 synthesis, colonic damage scores, and colon wet weight when examined at four days and two weeks [49]. The healing produced was deemed comparable to that achieved with 5-ASA treatment.

Imperial Chemical Industries has developed a series of heterocyclic cyclic ethers possessing 5-lipoxygenase inhibitory activity. These agents are available in parenteral, oral, and aerosolised forms. One of these compounds, 4-ethyl-2,2-dimethyl4(3-(3-(2-pyridyl)prop-2- ynlyoxy)-phenyl)-l,3-dioxolane is reported to have an IC50 of 0.8 pM against LTB4 and > 40 pM against TXB2 [201]. The same company has developed a series of novel heterocyclic cycloalkane derivatives that also inhibit 5-Bpoxygenase and are devoid of cyclooxygenase activity. A specific compound, fraans- 1,2-dimethoxy- 1 -(3-(3-(2-pyridyl)prop-2-y- 1 - 1yoxy)-pheny1)cyclopentane is reported to have an ICso of c 100 mgkg against LTB4 [202].

Terumo Kobushilci Kaisha has developed a series of novel substituted catechols which are 5-lipoxygenase inhibitors. The most potent compound 1 -(3,4-dihydroxyphenyl)-l -dodecen- 3,5-dione has an ICso of 1.2 x 10-7 M. These compounds have demonstrated the ability to inhibit ulcer formation in an ethanol hydrochloric acid model of rat gastric ulcer. The most potent compound, 1-(3,4-dihydroxyphenyl)-3,5-tetradecane dione, inhibited ulcer growth by 92.1% [203].

Tra n sloca t ion in h i bit o rs 5-lipoxygenase inhibition for some compounds has been shown to be dependent on an 18KD, a membrane protein referred to as 5-lipoxygenase activating protein (FLAP) [50]. Merck, Sharpe and Dohme has developed a class of leukotriene inhibitors, exemplified by MK886, which inhibits cellular translocation of cytosolic 5-lipoxygenase to a membrane fraction following ionophore activation.

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618 Overview - Inflammatory Bowel Disease Therapy - Carlson, Mutthy

L663,536 an orally active inhibitor of 5-lipoxygenase has demonstrated irreversible inhibition of LTB4 biosynthesis [30] with an IC50 of 0.02 pM. In the TNBS model of rat colitis, a single dose of L663,536 (10 mg/kg) inhibited colonic LTB4 biosynthesis by greater than 80% for up to 24 hours. Additionally, colonic damage scores and myeloperoxidase activity were decreased in the same model, if drug administration occurred early in the inflammatory process [42].

LTB4 receptor antagonists LTB4 is one of several stimuli of neutrophil activation. Cell adhesion, degranulation, and chemotaxis is dependent upon an LTB4 receptor. This LTB4 receptor has been characterised and represents a suitable target for anti-inflammatory agents.

Hoffinann-La Roche has isolated a high-affinity LTB4 receptor on pig neutrophils [51]. Using this receptor they have been able to demonstrate the anti-inflammatory activity of dietary fatty acids. Human neutrophil membranes were also employed to demonstrate LTB4 inhibition. This was greatest with linolenic acid and 6-linolenic acid.

Searle has formulated a potent LTB4 receptor antagonist SC-41930. This agent has been shown to attenuate intestinal mucosal inflammation in several models of rodent colitis, In a rat model of acetic acid-induced ileitis, an oral dose of SC 41930 (50 m a g ) was administered 30 minutes before and 30 minutes after the induction of ileitis. Myeloperoxidase and LTB4 levels were assessed 24 hours later in whole homogenates of ileum. Results indicated a reduction of myeloperoxidase and LTB4 levels to those of controls treated with vehicle alone [52]. The same compound inhibits adhesion of human PM"s to cultured human umbilical vein endothelial cells stimulated by LTB4, fh4LP, and PMA. This inhibitory effect occurs via selective antagonism of LTB4 receptors and is apparently ten times more sensitive than its chemotactic abolition response [53]. Interestingly, this compound abolishes LTB4/PGE2 production in the absence of infiltrating PM"s in guinea pigs. It is 3400 times less potent than indomethacin in inhibiting PGE2 production and is also capable of inhibiting human PMN superoxide generation [54].

Thromboxane A2 inhibitors Thromboxane A2 (TXA2) is the major product of arachidonate metabolism in platelets [55]. Produced via the cyclooxygenase pathway, TXA2, or more accurately its stable breakdown product, TxB2, is markedly increased in incubations of mucosal biopsies from patients with active ulcerative colitis and Crohn's disease [56,57]. The luminal concentration of this and other eicosanoids (i.e. PGE2, LTB4) is always increased in active disease and returns to normal levels in inactive disease [58]. Animal models bear out this observed increase in TxB2 levels in acute disease [59,60]. Given the presumptive role of TXA2 in acute relapses of IBD, the role of TXAz inhibition has been explored. One of the severa1 modes of action posited for sulfasalazine and 5-ASA is thromboxane synthesis inhibition [6 1,621.

TXA2 inhibitors can be conveniently divided into synthesis inhibitors and receptor antagonists. Synthesis inhibitors include Dazmegral which causes partial inhibition of C5a and fMLP-induced contraction of human umbilical artery [63]. CGS 12970 (3-methyl-2-(3 pyxidyl)-1-indole octanoic acid when administered to beagles at B dose of 30mgkg has demonstrated a 97% inhibition of TXB2 generation within two hours [ a ] . The thromboxane synthetase inhibitor OKY-046 has been shown to inhibit cyproheptadine-resistant contraction

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Anfi-inflarnrnafories etc. 61 9

by supernatants of intact canine basilar arteries [65]. The synthetase inhibitor CGS 13080 has demonstrated reversal of clinical manifestations of toxaemia in an ovine model [66].

Receptor antagonists include Squibb’s SQ29548, and SQ30741. The latter has demonstrated reversal of vasoconstriction in ovine models of pulmonary hypertension [67]. SQ29548 and daltroban (BM 13505) are capable of inhibiting conjunctival microvascular permeability induced by U-46619, the TP (thromboxane/prostaglandin) receptor agonist [68].

Nutritional modifications may also affect thromboxane levels. Specifically, TXB2 production can be decreased by feeding carnitine and acetyl carnitine in rat models of caregeenan elicited peritoneal macrophages [69]. Determination of the role of TXA2 antagonism in IBD awaits further human and animal studies.

Substrate inhibition The therapeutic effects of 5-ASA and sulfasalazine may be mediated by inhibition of arachidonic acid metabolism and subsequent formation of LTB4 [ 111. Substrate inhibition of arachidonate metabolism presents itself as a therapeutic option. McCall and colleagues have demonstrated histological and clinical improvement in six patients with ulcerative colitis with the use of eicosapentaenoic acid (EPA), a specific competitive inhibitor of arachidonic acid metabolism [70]. EPA has also been shown to be beneficial in four of five patients with steroid-resistant ulcerative colitis. Remission was obtained apparently after four weeks of a diet containing four grams EPA daily [71].

CD554 and CD58l are analogues of arachidonic acid which have been shown in viho to inhibit formation of lipoxygenase products of arachidonate metabolism. In addition they have been shown to decrease oedema formation and PMN migration in vivo in animal models [41]. While ostensibly useful as topical dermatologic agents, their substrate inhibition may prove useful in altered form for mucosal inftammation. ’

Immunomodulators/immunosuppressants 6-Mercaptopurine (6-MP) and azathioprine are immunosuppressive agents that have proven efficacious in selected cases of IBD. The mechanism of action of these agents is presently unknown, but some observations have been made. 6-MP in Crohn’s disease affects several lymphoid subpopulations resulting in decreased natural killer (NK) activity [72]. Additionally, a decrease in NK cell activity has been demonstrated in multiple sclerosis patients treated with azathioprine. Onset of this action was noted after one month of treatment with the nadir of response at four to five months [73]. However, no increase in NK cell activity has been demonstrated in inflamed tissues [74]. Increased cytotoxic T-cell activity has been shown in IBD with suppression of the activity by 6-MP maximal at four months [75].

Although the mechanism of action has not been fully elucidated, clinical studies have demonstrated efficacy. W o studies have demonstrated maintenance of remission using azathioprine in Crohn’s disease [76,77]. A steroid-sparing effect has been demonstrated in patients with chronic ulcerative colitis [78]. Another clinical trial showed a 73% response rate in refractory patients with ulcerative colitis, noted only after three months of therapy [79]. 6-MP has again been shown to be efficacious in patients with Crohn’s disease who had failed standard treatment. Skty-seven percent showed improvement with fistula closure, and a steroid-sparing effect in 75%. These effects again were only demonstrated after at least three months of therapy [80]. There is significant toxicity associated with 6-MP/azathioprine therapy. This

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620 Overview - Inflammatory Bowel Disease Therapy - Carlson, Miifthy

includes leukopenia, pancreatitis, hypersensitivity and hepatitis. Given these drawbacks these agents should be reserved for patients who have failed standard treatment protocols.

In the National Cooperative Crohn’s Disease Study over 20% of patients were unable to achieve remission despite seventeen weeks of treatment with predinosolone [83]. It has been suggested that these patients among others might benefit from the therapeutic use of the non-cytotoxic immunosuppressant, cyclosporin A (CsA) [82-851. Cyclosporin A is a cyclic polypeptide that acts specifically on T-helper cells by inhibiting growth factors such as IL-2 which are necessary for B-cell and cytotoxic T-lymphocyte differentiation and proliferation [85]. CsA appears to reduce IL-2 proliferation of T-lymphocytes by way of a post-receptor mechanism[88].

The efficacy of CsA has been demonstrated in a unique model of experimental colitis utilising dextran sulphate [87]. Intracolonic CsA has been shown to reduce disease activity indices from 2.5 f 0.7 to 0 after eight days of treatment. This was in contrast to oral CsA, 5-ASA enema and cortenemas which failed to improve disease activity indices and histological score [88,89]. That intracolonic CsA may find utility in humans has been demonstrated by high tissue levels of CsA and negligible serum levels in healthy volunteers treated with intrarectal instillation of CsA [go]. CsA has been tested in eleven patients with Crohn’s disease and two patients with ulcerative colitis [91]. This was in addition to their previous medical regimen and demonstrated apparent clinical improvement in all but one patient. Commonly noted side- effects include hypertrichosis, tremor, and hyperesthesia. Hypertension and epigastric pain were noted in only one patient.

FK-506 is a novel macrolide isolated from strains of the soil fungus, Sh-eptomyca tsukubaemh [92]. This compound is a potent immunosuppressant at concentrations 100 times less than CsA [93]. Its immunosuppressant action depends on the ability to modify activation of T-helper cells. In viaw this agent inhibits IL-2 receptor expression, mixed lymphocyte reaction, cytotoxic T-cell generation, and production of T-cell-derived soluble factors such as IL-2, IL-3 and IFN-ti [94]. Single dose treatment with FK-506 at 10 mgkg from day 3 to day 15 in type I1 collagen-induced arthritis suppressed ongoing immune responses and decreased clinical manifestations of arthritis in rats [95]. Whether FK-506 will find utility as an immunosuppressant in IBD in the same fashion as CsA remains to be seen.

Cytokine inhibitors There are several polypeptides that exert a major influence on the inflammatory process, Collectively referred to as cytokines, the most relevant of these are interleukin-1 (IL-1) and tumour necrosis factor (TNF). The availability of gene-cloned recombinant products has led to the development of ligand binding assays and subsequent pharmacological inhibitors,

Interleukin-1 is produced by virtually all nucleated cell types [96]. TNF on the other hand is produced only by monocytes and macrophages [97]. The biological activity of both pep- tides is nearly identical. Additionally, TNF can induce IL-1 release [98]. IL-1 and TNF have numerous cell targets and via those targets they can increase vascular permeability, increase neutrophilic adherence to endothelium [99] induce respiratory burst in neutrophils and monocytes [ 1001, induce release of proteoglycans and collagenase [ 1011, endogenous pyrogens [ 1021 and increase hepatic synthesis of acute-phase plasma proteins. Additional amplification of the immune system occurs via induction of IL-2 [ 103 3. Natural inhibitors of IL-1 exist in urine [lo41 and neutrophils [105]. Modulation of the potentially negative effects of IL-2 appears to be propagated via prostaglandin produc-

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Anti-inflammatories etc. 621

tion. Researchers have demonstrated PGE2 levels are increased with IL-1 pretreatment of colonic mucosa [ 1061. It has been subsequently shown that pretreatment of rabbits with IL-lp increased PGE2 and decreased the degree of inflammation in formalin-induced immune-com- plex colitis [107]. The Cotton-top tamaM model of colitis, considered the most similar to human IBD has shown, by RIA, increased levels of colonic IL-lp [ 1081. Increased plasma and tissue interleukin-2 receptor levels have been demonstrated in patients with Crohn’s disease and ulcerative colitis and appear to correlate with disease activity in the former [109]. Given the rather compelling evidence for the influence of cytokines in inflammation, researchers have developed a number of IL-1 and 1L2 inhibitors and receptor antagonists. Wyeth-Ayerst Research has developed a selective IL- 1 inhibitor, WY-48,989. This compound has shown preferential inhibition of IL-1 stimulated release of neutral proteases from chon- drocytes and also metalloproteases [ 1 lo]. As alluded to earlier FK-506 represents a potent IL-2 inhibitor. Parke-Davis has demonstrated CI-959 as a novel IL-2 inhibitor. This compound has been shown to block release of IL-2 fiom concanavalin A-stimulated rat spleno- cytes (IC5p19.1 pM) and human peripheral blood lymphocytes (ICs0=29.9 f 5.8 pM) [ 11 I]. Receptor inhibitors include IL-1 p mentioned above and Hoffmann-La Roche’s IL- Ira. The latter compound was tested in the rat acetic acid-induced colitis model. IL-Ira decreased colonic myeloperoxidase by 53 f 17% and decreased gross necrosis by 100 f 4% suggesting efficacy for the acute inftammation of relapsing IBD [ 1121.

PAF antagonists The role of platelet-activating factor (PAF) in gastrointestinal inflammatory disease was suggested by the profound shock and gastrointestinal infarction produced in dogs by infusion of that compound [ 113 1. Formation of PAF occurs by a two-step process: (1) activation of phosphoIipase A2 (same as that in arachidonate metabolism) and deacylation to lyso-PAF and (2) acetylation by acetyltransferase to PAF [ 1141. Formation of PAF accompanies stim- ulation of PMN’s, platelets, and vascular endothelial cells and activates eosiaophils, PM”s and platelets. It has been demonstrated that colonic tissue from patients with ulcerative colitis releases significantly more PAF than controls when incubated in vim [ 1151. PAF levels have been shown to be sixteen times higher than controls one to three weeks following induction in the hapten-induced (TNBS) model of rodent colitis [ 1161. This suggests a role for PAF at least in the chronic phase of IBD.

Specific PAF antagonists have been produced with the intention to attenuate PAF levels and tissue injury. In a rat model of hapten-induced colitis the specific PAF inhibitor BN52021 reduced colonic damage scores and wet weight of distal colon [i17]. This effect was noted if treatment was instituted in the first two weeks but not in the first four days suggesting again the role of PAF in IBD chronicity. The role of PAF as a pro-inflammatory mediator and neutrophil chemoattractant was studied in the acetic acid-induced model of rodent colitis [118]. Therein PAF levels were noted to increase from 139 mg/g f 29 mg/g to 248 mg/g i 39 mglg in acetate-inflamed tissues. Unique PAF antagonists, WEB 2086 and Ro24-0238, demonstrated 53% and 43-47% inhibition, respectively, of PMN accumulation in that model.

The Societe de Conseils de Recherches et d’ Applications Scientifiques (SCRAS) has disclosed a series of thieno-triazolo-diazepine derivatives which exhibit potent PAF antagonistic activity 10 to 1000 times greater than any similar species described €2041. PAF-inhibitory activity was demonstrated via decreased platelet aggregation in male New Zealand rabbits (ICso = 1.7 x 107 to 9.22 x lO-gM) and inhibition of bonding to benzodiazepine receptors. Similar compounds were shown to inhibit bronchoconstriction activity [ 1-51, Putative inhibitors of

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622 Overview - inflammatory Bowel Disease Therapy - Catison, Murthy

PAF including dexamethasone and ketotifen are being studied in the rat model of endotoxic shock [116]. Necessarily human trials with PAF antagonists will decide their utility in IBD.

Anti-oxidants and free radial scavengers There is compelling experimental evidence that oxygen free radicals play an important role in mediating the inflammation found in gastrointestinal disease. Activated neutrophils, eosinophils, monocytes,and macrophages release fiee radicals with a respiratory burst to anni- hilate pathogens. Exaggeration of this beneficial effect of free radical formation is postulated to cause cellular injury. The major fiee radical species include the superoxide radical and the hydroxyl radical. A number of enzymes are known to produce the superoxide radical as a reaction product. Major enzymes include xanthine oxidase and NADPH oxidase which can be found in the intestinal phagocytic cells, endothelial cells and mucosal epithelium. Metabolism of the superoxide radical to hydroxyl radical in the presence of 8 metal catalyst such as iron via the Haber-Weiss reaction potentially endangers cell integrity. The hydroxyl radical is toxic via several mechanisms: (1) oxidation of sulphydryl compounds that may result in enzyme inactivation; (2) DNA damage [119]; (3) potentially malignant transformation [ 1201 and (4) lipid peroxidation [121]. Interestingly, the metabolism of arachidonic acid represents a mode of lipid peroxidation as well [60].

Several compounds are purported to help stop oxygen free radical damage. Major enzymes involved include superoxide dismutase (SOD), catalase and glutathione peroxidase. Non- enzymatic fiee radical scavengers include a-tocopherol, ascorbic acid, ceruloplasmin, p- carotene, allopurinol, mannitol [122] and mucins [ 1231.

Sulfasalazine and 5-ASA may derive some of their efficacy from their free radical scavenging properties [124,125]. 5-ASA and to a lesser extent 4-ASA have been shown to prevent L- cystine oxidation by NH2Cl in vibo [ 1261. NH2Cl is a chlorinated oxidant which is produced along with HOCl via a myeloperoxidase-catalysed reaction and is known to cause alteration in intestinal mucosal function.

Wolfson Research Laboratories has developed a novel organo-selenium compound, Ebselen, which significantly decreases lipid peroxide formation h a rat paw model of H202-hduced injury [ 1271.

As noted above, superoxide dismutase (SOD) represents one of the first line anti-oxidant compounds h the human body. Clinical application of SOD as a therapeutic agent is limited by its short half-life (tl/2 = 5 minutes), instability, and immunogenicity in vivo. A novel SOD pyran polymer conjugate has been developed which remains in plasma for five hours after injection without provoking immune reactions [ 1281.

The Upjohn Company has developed a series of 21-aminosteroids which are very potent inhibitors of lipid peroxidation. Widened human trials of their U74-006F as a treatment for head injury are underway [ 1291. A single report suggests that administration of SOD may attenuate some of the tissue damage of Crohn’s disease [ 1301. Additional trials have demonstrated similar efficacy in ulcerative colitis [131]. It is postulated that the beneficial effect of D-penicillamine in a few patients with Crohn’s disease may be via its free-radical scavenging properties [ 1321.

In vivo formation of free radicals is dependent in part on the presence of xanthine oxidase. Boehringer Ingelheim has developed a series of novel 1,2,3-triazolo-pyrido (2,1 A ) quina- zolines possessing xanthine oxidase inhibitory activity [206]. These compounds have been

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shown to have iii vibr, inhibitory activity far exceeding that of allopurinol (K, = 2.1 x 10-9 to 4 . 1 ~ 10" m o m compared to 2.1 x 10-6 for allopurinol). Whether this series of compounds prove useful in human IBD awaits further testing.

Non-enzymatic inhibition of fiee radicals has been demonstrated for a-tocopherol, ascorbate, uric acid, methionine and carotenoids [133]. a-Tocopherol quinone, an in vivo metabolic product of vitamin E and ferrous sulfate has been shown in at least one case to cause remission of ulcerative colitis when other therapeutic modalities had failed [ 1341. The G.I. mucosa contains high concentrations of SOD, catalase, glutathione and a-tocopherol [ 1331. Purified much has been shown to scavenge hydroxyl radical suggesting a protective role for the G.I. mucosa against fiee radical damage [123]. An artificial composition containing a mixture of polar and neutral phospholipids may be useful for protection of gastrointestinal luminal surfaces especially in gastrointestinal ulceration and IBD. The University of Texas has developed just such a series of mixtures that have been demonstrated to enhance the protective effect against acid-induced gastric ulcerogenesis in rats [207]. Further studies are mandated to evaluate efficacy in human IBD.

Summary Although the etiology of IBD is unclear, progress has been made in identifymg the cells and the mediators that cause inflammatory response. The inflammatory cells and the biochemical mediators that are evidenced in excess, the enzymes that are activated and the receptors that bind these mediators during 'acute' exacerbation of IBD appear to be pathologically similar to inflammation observed in various other organ systems. Progress has been made in modifying the empirical therapy with 5-ASA and its congeners suitable for topical therapy as enemas. Oral therapy with 5-ASA has also met with changes by complexing it with less toxic pharmaceutical adjuvants for delivery to target areas. Progress in steroid therapy has focused on not only increasing the glucocorticoid activity, but also chemically modifying corticosteroids such that they are absorbed less readily and rapidly metabolised to reduce their adverse side- effects. The use of cyclosporin and azathioprine has met with some success. However, recent progress in understanding inflammatory diseases in pharmacological terms has provided an impetus for pharmaceutical companies to discover novel therapies to combat the disease by preventing the production or binding of inflammatory mediators to their respective receptors. It is too early to predict how efficacious these drugs will be in suppressing the inflammatory response. Clearly more controlled studies are needed to substantiate the efficacies of these drugs. Be that as it may, recent enthusiasm emerging fiom the discovery of novel therapeutic agents to combat inflammation in general has changed the trends in IBD therapy. The next few years will tell whether these drugs are therapeutically useful and whether a single drug is efficacious to combat both Crohn's disease and ulcerative colitis.

References to primary literature

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a!.: Inflammatory mediators in cotton-top 121. AUST SD, SVINGEN BA: The role of iron in tamarins with acute and chronic colitis. enzymatic lipid peroxidation. In: Free Radicals Inflammation Research Association, 5th Intema- in Biology, WA Prior ed, Academic Press (1982)

110. DIJOSEPH JF, CACCESE RG, SKOTNICKI JS ef a/.: 122. HOOPER C: Free radicals: Research on bio- Inhibition of interleukin-l(lL-I) induced neu- chemical bad boys comes of age. The Joulnal

cytes by WY-46,135 and WS-48,989. Inflam- 123. GRKHAM MB, VON RTIER C. SMITH BF e? af.: mation Research Association, 5th International Interaction between oxy radicals and gastric Poster Session (1990) 178. mucin. Am. J. Physiol. (1987) 253:G93-G96.

111. DONG MK, WILBURN DJ, CONROY MC,

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109. CLAPP NK, HENKE MA, HANSARD RM et einogens. Scieme (1983) 221 : 1256-1 264.

tional Poster Session (1990) 142. 1-28.

tral proteases from rabbit articular chondro- of NfH R ~ ~ e ~ i r h (I 989) 1 : 10 1 - 106.

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124. HALLIWELL B: Sulfasalazine and oxidant scav- 129. HALL ED, PAZARA KE, BRAUGHLER JH: 21- enging in ulcerative colitis. Lancet ( I 987) Aminosteroid lipid perixidalion inhibitor 12:635. U74006F protects againsl cerebral ischaemia

Actions of sulfasalazine and SASA as reac- 130. EMERITT J, LOEPER J, CHoMETTE G: Super- tive oxygen scavengers in the suppression of oxide dismutases in the treatment of post bile acid-induced increases in colonic epithe- radiotherapeutic necrosis and of Crohn’s dis- lial cell loss and proliferative activity. Gas% ease. Bull. Eur: Pliy.siciputltol. Respir: ( I98 I )

126. TAMAI H, KACHUR JF, GRKHAM MB, GAGINELLA 131. PERKAU A: Scientific basis for the clinical TS: Neutrophilderived oxidants are scav= use of superoxide dismutase. Cancer 7kitniait enged by SASA: possible relationship to its Review (1 986) 13: 17-44. therapeutic action in inflammatory bowel dis= 132. EMERIT 1, EMERIT I, LEUG A, BECK M: Chro- ease. Inflammation Research Association, 5th mosomal breakage in Crohn’s disease: Anti- International Poster Session (1 990) 17. elastogenic effect of D-penicillamine and G

127. DOWLING El, GRJFFITHS HR, LUNEE J, BLAKE cysteine Huntair Geitetics ( 1 972) 16:3 13-322. DR: Oxidative damage to lipids, protein, and 133. GRlSHAM MB, GRANGER DN: Neutrophil- carbohydrate in an animal model of inflam- mediated mucosal injury - role of reae- mation: Protection by Ebselen. Inflammation tive oxygen metabolites. Dig. Dis. Sci. (1988)

Session (1990) Abstract #193. 134. BENNETT J D Use of a-tocopherolquinone in 128. ODA T, AKAIKE T, HAMAMOTO T et al.: the treatment of ulcerative colitis. Gut (1986)

125. CRAVEN PA, PFANSTIEL J, SAJTO R et al.: in gerbils. Sfrvke ( I 988) 19:997- 1001,

~ I O & C I ~ O ~ Y ( I 987) 92: 1998-2008. 17:287-288.

Research Association. 5th International Poster 33~6S-15S.

Oxygen radicals in influenza-induced patho- 27:695-697. genesis and treatment wilh pyran polymer- conjugated SOD. Science ( 1 989) 244:974-976.

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overview: new directions in inflammatory bowel disease therapy

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