Systematic review: coxibs, non-steroidal anti-inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high-risk patients?

Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.

Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part I).

Drug treatment of gastrointestinal diseases, which was previously limited to the use of antacids, anticholinergics, antispasmodics, cathartics and laxatives, has changed markedly over the past decade. Histamine H2-receptor antagonists (e.g. cimetidine, ranitidine and more recently famotidine and nizatidine) have revolutionised the treatment of peptic acid disorders, but their role is currently challenged by muscarinic-M1-receptor antagonists (e.g. pirenzepine), proton pump inhibitors (e.g. omeprazole), prostaglandin analogues and site-protective drugs (e.g. colloidal bismuth subcitrate and sucralfate). Newer antiemetics with prokinetic properties (e.g. metoclopramide, domperidone and cisapride) have also been introduced in the management of gastrointestinal motility disturbances, and new anti-inflammatory salicylates (e.g. olsalazine and mesalazine) have been developed for the treatment of chronic inflammatory bowel diseases. Finally, diphenoxylate and loperamide have gained wide clinical application as nonspecific antidiarrhoeal agents. The basic pharmacokinetic properties of the above agents are briefly reviewed with the main emphasis on the newer and more important drugs in current use. Furthermore, the effects of age and disease on pharmacokinetics, in addition to drug interaction potentials and pharmacokinetic-pharmacodynamic relationships, are discussed. The anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics will be dealt with in Part II.

Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part II).

Part I of this article, which appeared in the previous issue of the Journal, covered the following agents: histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine); muscarinic-M1-receptor antagonists (pirenzepine); proton pump inhibitors (omeprazole); site-protective agents (colloidal bismuth subcitrate, sucralfate); antacids and prostaglandin analogues; antiemetics and prokinetics (metoclopramide, domperidone, cisapride); and antispasmodics. In Part II, we consider the anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics.

Review: clinical trials in peptic ulcer disease--problems of methodology and interpretation.

This review focuses on the methodology and interpretation of drug trials in peptic ulcer disease. The problems of planning and conduct that are discussed include the ethics of using placebo, eligibility criteria, estimations of sample size, stopping rules, randomization, blinding, and efficacy criteria, that is, ulcer healing and pain relief in the short term and prevention of relapse and complications in the long term. Statistical topics covered include confidence intervals, evaluation of survival type data, post-stratification, and sub-group analysis. The difference between clinical and statistical significance is discussed, major problems being overemphasis on P-value, type II errors, and post hoc power determinations. Explanatory and pragmatic questions are based on compliance-to-protocol and intention-to-treat cohorts, respectively, and involve problems of compliance testing, evaluation of withdrawals, and the use of fixed-dose regimens. The rather slow process for clinical trials to gain acceptance is described, and it is proposed to rely on disease-related and behavioural barriers, lack of knowledge of the inherent limitations of methodology, and overemphasis on the subject of peptic ulcer healing, in addition to some concern at the relevance of assessing long-term drug intervention by repeated endoscopies rather than by studying symptoms and the incidence of complications. We foresee an increased impact of clinical trials on ulcer research and therapeutic decision making, provided physicians are able to develop the proper methodology to answer the relevant questions.

Review article: the potential role of nitric oxide in chronic inflammatory bowel disorders.

The aetiology of the chronic inflammatory bowel diseases-ulcerative colitis and Crohn's disease-as well as 'microscopic colitis'-both collagenous (COC) and lymphocytic colitis (LC)-remains unknown. Autoimmune mechanisms, cytokine polymorphism, commensal bacteria, infectious agents and vascular impairment have all been proposed as playing important roles in the pathogenesis of this spectrum of diseases. A variety of proinflammatory mediators, including tumour necrosis factor alpha, interleukin-1beta, interferon gamma, leukotriene B4 and platelet activating factor, promote the adherence of phagocytes to the venular endothelium and extravasation of these cells into the colonic mucosa. In addition to large amounts of nitric oxide (NO), injurious peroxynitrite may be formed in the epithelium by the inducible nitric oxide synthase (iNOS), which is considered to elicit cytotoxicity by the generation of superoxide with reduced L-arginine availability. In active ulcerative colitis, and to a lesser extent in Crohn's disease, a greatly increased production of NO has been demonstrated by indirect and direct measurements. Surprisingly, even higher rates of production have been observed in COC-a condition which is never associated with injurious inflammation. The latter observation favours the notion that NO promotes mucosal integrity. Further evidence for a protective role of NO in chronic inflammatory bowel disorders is provided by the observation of increased susceptibility to the induction of experi mental colitis in 'knock-out' mice deficient in iNOS. Selective inhibitors of iNOS activity, as well as topical L-arginine, may therefore prove beneficial in inflammatory bowel disease by reducing the production of superoxide by iNOS, while only the former option may be expected to reduce diarrhoea in chronic inflammatory bowel disorders. Clearly, further experimental work needs to be done before testing topical L-arginine in human inflammatory bowel disease.

Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine.

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

Colloidal bismuth subcitrate causes sustained release of gastric mucosal prostaglandin E2.

Gastric application of high doses of colloidal bismuth subcitrate (CBS) stimulates mucosal prostaglandin E2 (PGE2) production, which is considered part of the mechanism by which the drug accelerates peptic ulcer healing. Whether therapeutic, orally administered, doses of CBS cause a sustained stimulation of prostaglandin production is not known. We have, therefore, determined gastric luminal release of PGE2 during 'steady-state' perfusion of the stomach with CBS (10 mg/ml; isotonic mannitol 5 ml/min) and 4 h after the last oral dose of the drug (240 mg b.d.) for 2 weeks (isotonic mannitol 5 ml/min) in 8 healthy volunteers. A significant increase in PGE2 concentrations (712 (409-1076) vs. control 334 (252-655) pg/ml; medians with Q50 ranges; P less than 0.02) and PGE2 output (12.5 (7.3-14.3) vs. control 4.8 (4.1-7.3) ng/15 min; P less than 0.02) occurred during gastric perfusion with CBS. A similar increase in PGE2 concentrations (630 (297-1429) pg/ml; P less than 0.02) and PGE2 output (12.6 (6.4-22.2) ng/15 min; P less than 0.02) was observed following treatment with CBS for 2 weeks. These results suggest that therapeutic doses of CBS cause a sustained stimulation of gastric mucosal PGE2 formation.

Effect of 10 mg and 20 mg omeprazole daily on duodenal ulcer: double-blind comparative trial.

One-hundred and seventy-one patients with endoscopically proven duodenal ulcers were allocated at random to double-blind treatment with 10 or 20 mg of omeprazole in the morning for up to 4 weeks. Patients completed the study if ulcer healing and pain relief had occurred at 2 weeks. A total of 155 patients completed the trial. Patients treated with 20 mg of omeprazole daily responded significantly more rapidly than those treated with 10 mg of omeprazole daily (P less than 0.001; Cochran-Mantel-Haenszel test covering both time points), cumulative healing rates at 2 and 4 weeks were 74% (58/78) and 91% (71/78), respectively. The corresponding rates in the group treated with 10 mg daily were 48% (39/81) and 75% (58/77). Pain relief was again more pronounced during treatment with the larger dose (P less than 0.05; stratified Wilcoxon test). No major clinical or biochemical side effects were noted. An omeprazole dose of 20 mg daily is preferable to a lower dose for the treatment of duodenal ulcer disease in the short term.

High glucose impairs superoxide production from isolated blood neutrophils.

OBJECTIVE: Superoxide (O(2)(-)), a key antimicrobial agent in phagocytes, is produced by the activity of NADPH oxidase. High glucose concentrations may, however, impair the production of O(2)(-) through inhibition of glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the formation of NADPH. This study measured the acute effects of high glucose or the G6PD inhibitor dehydroepiandrosterone (DHEA) on the production of O(2)(-) from isolated human neutrophils. DESIGN: Laboratory studies of short-term cultures of neutrophil granulocytes. PARTICIPANTS: Healthy subjects. INTERVENTIONS: Neutrophils were isolated from peripheral blood and incubated for 1 h in Krebs-Ringer buffer containing 5, 10, or 25 mM glucose, 5 mM glucose with 0, 5, or 20 mM mannitol, or 5 mM glucose with 0, 1, 10, or 100 micro M DHEA. O(2)(-) production was induced by N-formyl-methionyl-leucyl-phenylalanine and measured by the cytochrome c reduction assay. Potential scavenging of O(2)(-) by glucose, mannitol, or DHEA was assessed in a cell free system using the pyrogallol assay. MEASUREMENTS AND RESULTS: Incubation of neutrophils with glucose dose-dependently reduced O(2)(-) production, which was 50% decreased at 25 mM glucose. Also DHEA reduced the production of O(2)(-) dose-dependently, whereas production rates were unaffected by mannitol. Neither glucose, mannitol, nor DHEA scavenged O(2)(-). CONCLUSIONS: High extracellular glucose concentrations acutely reduce O(2)(-) production from activated neutrophils possibly through inhibition of G6PD. If this occurs in vivo, microbial killing by neutrophils may be impaired during acute hyperglycemia, as observed after major surgery, trauma, or severe infection.

From basic science to future medical options for treatment of ulcerative colitis.

Both ulcerative colitis (UC) and Crohn's disease are considered the result of an unrestrained inflammatory reaction, but an explanation for the aetiopathogenesis has still not emerged. Until the predisposing and trigger factors have been clearly defined, therapeutic and preventive strategies for these disorders must, therefore, rely on interrupting or inhibiting the immunopathogenic mechanisms involved. Current therapies, such as glucocorticoids and 5-aminosalicylic acid, inhibit raised concentrations of interdependent, soluble mediators of inflammation, which may amplify one another or have parallel effects. Future medical options for treatment of UC aim at removing perpetuating antigens, blocking entry of inflammatory cells by manipulating adhesion molecules, targeting soluble mediators of inflammation by blocking proinflammatory molecules or by preserving endogenous suppressive molecules, or correcting genetic defects. It remains, however, to be determined whether targeting multi-inflammatory actions or a single key pivotal process is the better therapeutic strategy and whether subgroups of UC with different clinical courses will require different treatment approaches.

IOIBD questionnaire on the clinical use of azathioprine, 6-mercaptopurine, cyclosporin A and methotrexate in the treatment of inflammatory bowel diseases.

OBJECTIVE: To obtain information on the clinical experience with azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the treatment of patients with inflammatory bowel disease (IBD) by gastroenterologists and internists in different countries. DESIGN: A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living in North America (n = 76) and Europe (n = 224) (12 countries), to obtain information on clinical experience. PARTICIPANTS: More than half of the respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in general (non-university) hospitals. Two-thirds (65%) had more than 10 years' experience in gastroenterology. RESULTS: The respondents had personal experience with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6-MP less frequently by the European than the North American respondents (23.8 and 53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA together with steroids to Crohn's disease patients; 62.4% of the respondents prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9% had experience with AZA (Europe > North America, P = 0.0001). AZA had been prescribed by 69 respondents to pregnant patients, without apparent toxicity. Acute pancreatitis had been observed after AZA by 56.7% respondents; 25 malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer, four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by 33.9% in Europe (not significant). Several significant differences were observed between the prescription behaviour of respondents working at university hospitals and non-university hospitals, in particular in relation to participation in clinical trials. CONCLUSIONS: Considerable experience exists in the use of immunosuppressive therapy in IBD; however, differential prescription behaviour exists in the choice of immunosuppressives between North America and Europe. These IOIBD study results may contribute to a better insight in the daily use of immunosuppressive agents in IBD by gastroenterologists and other specialists.

Cytoprotection of gastroduodenal mucous membrane with analogues of prostaglandins.

Analogues of E-type prostaglandins, such as arbaprostil, enprostil, misoprostol, rioprostil, and trimoprostil, suppress gastric acid secretion and (like native E-type prostaglandins) the chemically modified analogues enhance a number of gastroduodenal mucosal defence factors. These include regulation of the thickness and the composition of the mucous layer at the epithelial surface; modulation of active bicarbonate secretion; hydrophobicity of the surface epithelium; rapid cell proliferation and differentiation after mucosal damage; maintenance of interstitial bicarbonate; and the integrity of the mucosal microcirculation. In theory, this bimodal action makes prostaglandin analogues ideal drugs for treating and preventing lesions of the gastroduodenal mucous membrane. In practice, however, these expectations remain unfulfilled. First, in doses lower than those required to decrease acid secretion, prostaglandin analogues retain cytoprotective properties but are no better than placebo in healing peptic ulcers. Second, in fully antisecretory doses some prostaglandin analogues accelerate ulcer healing compared with placebo and provide healing rates about as high cimetidine, but less than achieved with ranitidine. Third, despite the fact that high doses of some analogues are superior to placebo in alleviating pain associated with ulcer disease, these agents proved inferior to cimetidine and ranitidine in relieving pain in most comparative trials. Fourth, enprostil and misoprostol in doses which combine antisecretory with cytoprotective properties perform significantly poorer than ranitidine in preventing relapse of peptic ulcer disease. Fifth, although several uncontrolled observations have suggested a therapeutic benefit of prostaglandin analogues in gastroduodenal haemorrhage, placebo-controlled trials show no effect of arbaprostil in stopping bleeding and in preventing rebleeding.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of eicosanoids in the gastrointestinal tract.

Exploring the role of eicosanoids in the gastrointestinal tract entails fundamental problems of methodology and interpretation. Most important are the difficulties inherent in the choice of an experimental design which prevents non-specific stimulation of eicosanoid formation, because any perturbation of cell membranes will initiate eicosanoid synthesis. In addition to cyclic nucleotides, prostaglandins may serve as intracellular mediators for the stimulus of secretion coupling via intracellular free calcium in the gastrointestinal epithelial cells. By contrast, the effects of supraphysiological doses of prostaglandins parallel those of cyclic AMP-dependent secretagogues such as VIP, which increases calcium through activation of the mucosal adenylatecyclase. The question of whether patients develop gastric or duodenal ulcers as a result of a prostaglandin deficiency remains open. The synthetic prostaglandin analogues available commercially for anti-ulcer therapy appear to be unable to accelerate the healing of peptic ulcers unless they are administered in anti-secretory doses, and are unlikely to have a substantial effect on patients with bleeding from ulcerative lesions in the gastro-duodenal mucosa. Prostaglandins of the E type mediate, at least partly, the diarrhoea associated with a large number of clinical conditions and various pharmacological agents. Several types of secretory diarrhoea respond to drugs that inhibit prostaglandin biosynthesis. Whether eicosanoids are mediators, or merely epiphenomena, of inflammation in ulcerative colitis and Crohn's disease remains unclear. Improved knowledge of their functional role of eicosanoids has nevertheless allowed a reinterpretation of the rationale behind current therapy. Uncontrolled formation of eicosanoids may not only be the source of diarrhoea in colonic inflammation, but may also be critical for cell proliferation and the development of dysplasia in long-standing disease.

Prostaglandins and chronic diarrhoea: methodological problems.

In order to determine the arterio-venous difference in circulating prostaglandin levels the isotope derivative technique was applied to rat plasma for measurements of prostaglandin E2 (PGE2). No arterio-venous difference was observed if the blood was collected without precautions to avoid in vitro prostaglandin production in the sampling tube. In contrast, inhibition of the in vitro prostaglandin release by the infusion of indomethacin into the catheter from which the blood was drawn, showed PGE2 levels in the right atrium of 60 +/- 20 pg/ml (mean +/-SD; N = 8), and peripheral levels insignificantly different from zero. A significant difference in PGE2 levels of right atrial plasma from fed and fasted rats was observed without the use of in vitro indomethacin in blockade (210 +/- 70 pg/ml; N=4, and 330 +/- 35 pg/ml; N = 4, respectively). This difference could not be reproduced if indomethacin was infused into the catheter (60 +/- 20 pg/ml; N = 8 and 90 +/- 35 pg/ml; N = 5, for fed and fasted rats, respectively). Measurements by radio-gas-liquid-chromatography of the arachidonic acid plasma level showed values of 6.8 +/- 1.6 micrometers (N = 7) and 12.0 +/- 3.4 micrometers (N = 7) for fed and fasted rats, respectively. It is suggested that the higher level of PGE2 (without indomethacin) in fasted rats reflects that of arachidonic acid. The present available methods for the determination of primary prostaglandins and prostaglandin metabolites are discussed with respect to their value not only in physiological studies on fluid and electrolyte transport in the gut, but also for clinical use.

Mediators of inflammation in chronic inflammatory bowel disease.

A distinguishing feature of inflammatory bowel disease (IBD) is its apparently spontaneous, chronic relapsing course. Despite extensive research over several decades the etiology of IBD remains unknown, but evidence has accumulated to suggest that the mucosal inflammatory response may be caused by (i) a defective mucosal barrier function resulting in an abnormally increased exposure to luminal antigens and toxins, (ii) an appropriate immunologic response to an unusual infection, antigen or toxin, or (iii) an inappropriate immunological response to ubiquitous antigens or stimuli. In recent years, the identification of established and potential mediators of inflammation has expanded to include eicosanoids, platelet activating factor, biogenic amines, kinins, complement-derived peptides, chemotactic peptides, cytokines, neuropeptides, and reactive metabolites of oxygen and nitrogen. Thus, the study of the inflammatory process has become ever more complex. Until the predisposing and trigger factors have been identified the achievement of a more rational and effective approach to therapy in IBD relies on interruption of the mechanisms responsible for excess mediator formation. As summarized in this review on the role of soluble mediators of inflammation, several Danish gastroenterologists have been profoundly engaged in basic and clinical research in the past 25 years to place some pieces of the confusing puzzle of IBD.

Prostaglandins and clinical experience in peptic ulcer disease.

Synthetic prostaglandin analogues of the E series offer a new approach to the medical treatment of peptic ulcer disease by combining antisecretory with cytoprotective properties, such as protection of the gastric mucosa against damage induced by aspirin. Controlled trials of prostaglandin analogues in peptic ulcer healing have failed to demonstrate any superiority to conventional treatment. Any beneficial effect is explicable by acid inhibition, and diarrhoea is a major and dose-limiting side effect. Non-antisecretory doses that are still said to be cytoprotective do not accelerate ulcer healing. Also, the prostaglandin analogues seem ineffective in the treatment of peptic ulcer haemorrhage. Thus the clinical relevance of cytoprotection by synthetic prostaglandins has not been established. Although antisecretory doses of some analogues may prove to be yet another approach to drug treatment, the present results do not forecast a new breakthrough in the management of peptic ulcer disease.

Colonic prostaglandin E2 levels and olsalazine metabolism in relapsing ulcerative colitis: implications for controlled trials in the long term.

To examine the tolerance and pharmacokinetics of long-term olsalazine administration, increasing doses of the drug were given to 31 patients with ulcerative colitis. All patients were refractory to or intolerant of sulphasalazine. Complete azo-reduction occurred in most cases. Concentrations of 5-ASA, but not acetyl-5-ASA, in faecal dialysates increased dose-dependently. Estimates of efficacy were more favourable among those intolerant of sulphasalazine. Patients with high prostaglandin E2 levels determined by equilibrium in vivo dialysis of rectum were less likely to benefit from treatment. In conclusion, olsalazine is a highly effective means of delivering 5-ASA to the colonic mucosa. Long-term use of olsalazine in controlled trials may be considered safe, even in high doses.