Protocols to assess the gastrointestinal side effects resulting from inhibition of cyclo-oxygenase isoforms.

A prevalent unwanted action of cyclo-oxygenase (COX) inhibitors, as exemplified by the non-steroidal anti-inflammatory drugs (NSAIDs), is their potential to produce gastrointestinal side effects in clinical use. The injury provoked by such agents includes rapid superficial disruption to the surface layer of the gastric mucosa, the production of acute gastric erosions in the corpus region and the formation of ulcers in the antral region of the stomach. The small intestine is also adversely affected, with a developing enteropathy over a more protracted period that causes lesions and inflammation in the gut.

New light on the anti-colitic actions of therapeutic aminosalicylates: the role of heme oxygenase.

Although a variety of pharmaceutical preparations of aminosalicylate are commonly used in the clinic for the control of inflammatory bowel disease, the mechanisms underlying their therapeutic actions remain unclear. Recent in vivo and in vitro studies have demonstrated that 5-aminosalicylic acid (5-ASA), regarded as the active moiety in aminosalicylate preparations such as sulfasalazine, can induce the heat shock protein, heme oxygenase-1 (HO-1) and up-regulate HO enzyme activity in the colon. As HO-1 can produce endogenous anti-oxidant and anti-inflammatory moieties such as bilirubin and carbon monoxide (CO), these findings suggest a novel mechanism of action for aminosalicylates, acting as anti-colitic agents through the up-regulation of HO-1 enzyme expression and activity.

The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis.

The mechanism of action of 5-aminosalicylic acid (5-ASA), the active therapeutic moiety of a number of clinically used anti-colitic agents, is unclear. The present study investigates whether the beneficial effects in vivo could involve induction of the heat shock protein, heme oxygenase-1 (HO-1), known to provide endogenous anti-oxidant and anti-inflammatory moieties which can modulate colonic inflammation. The effects of 5-ASA on the colonic expression and activity of HO-1 along with its effect on the inflammatory damage have been evaluated in the colitis provoked by instillation of trinitrobenzene sulphonic acid (TNBS) over 48 h in the rat.

Modulation by heme and zinc protoporphyrin of colonic heme oxygenase-1 and experimental inflammatory bowel disease in the rat.

Reactive oxygen species, suggested to be involved in inflammatory bowel disease, may be modulated by endogenous anti-oxidant products of heme oxygenase-1 (HO-1). In the present work, HO-1 expression in trinitrobenzene sulphonic acid (TNBS)-induced colitis in the rat and the effects of HO-1 modulation, particularly by the HO-1 inducer, heme, were further evaluated. Colitis was induced by intracolonic challenge with TNBS and assessed macroscopically and by myeloperoxidase (MPO) assay.

Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta.

The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.

Nitric oxide-modulating agents for gastrointestinal disorders.

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO-non-steroidal anti-inflammatory drugs (NO-NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed.

Endotoxin can decrease isolated rat parotid acinar cell amylase secretion in a nitric oxide-independent manner.

Salivary mucus and amylase have an anti-bacterial nature. Bacterial endotoxin is considered to decrease mucus secreting cell activity by nitric oxide-dependent mechanisms. In this study, the actions of endotoxin on amylase secreting cell activity have been studied.

Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat.

The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.

Cyclooxygenase and nitric oxide systems in the gut as therapeutic targets for safer anti-inflammatory drugs.

After a decade of intense pharmacological and drug development activity by the pharmaceutical industry, compounds derived from two key strategies for reducing gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) have been subjected to rigorous clinical appraisal. Despite the undoubted therapeutic and commercial success of the selective cyclooxygenase (COX)-2 inhibitors, known as the coxibs, with second-generation compounds already approved and launched, some concerns over their full gastrointestinal profile still linger, while the cardiovascular safety of this class has become a key issue. Likewise, Phase II evaluation of compounds incorporating a nitric oxide (NO)-donating moiety into standard NSAIDs (the NO-NSAIDs or CINODs) has created recent controversy over the full clinical profile of these compounds.

Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors.

By far the most attention has been paid to the deleterious actions of nonsteroidal anti-inflammatory drugs (NSAIDs), including isoform selective agents that inhibit cyclooxygenase (COX), on the upper gastrointestinal tract, particularly the gastric and duodenal mucosa. However, recent studies confirm a relatively high incidence of serious clinical events, especially with the more-established drugs of this class, involving the small intestine. Pathogenic factors that have been proposed from early studies in such enteropathy have included the enterohepatic circulation of the nonsteroidal anti-inflammatory drugs, inhibition of cyclooxygenase, surface epithelial changes and focal microvascular events.

Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs.

Nitric oxide (NO) can protect the gastrointestinal tract from injury, including that provoked by non-steroidal anti-inflammatory drugs (NSAIDs). This protective profile of NO, which predominantly reflects actions on the microcirculation, is mimicked by NO donors. Moreover, the NO-donating agents know as the NO-NSAIDs or CINODs (cyclo-oxygenase-inhibiting nitric oxide-donating drugs) exhibit reduced gut injury in experimental models, which is considered to reflect these local beneficial actions of NO.

Gastrointestinal effects of nonsteroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) causes extensive damage to the gastrointestinal (GI) tract. The underlying mechanisms of gastric injury include topical irritant actions that disrupt the epithelial barrier, as well as the inhibition of cyclo-oxygenase (COX), which is predominantly the COX-1 isoform in the mucosa. This damage can be attenuated by antisecretory agents or by mucosal protective agents such as the synthetic prostanoids or nitric oxide (NO) donors.

ONO-1714 (Ono).

Ono Pharmaceuticals is developing ONO-1714, a selective inducible NO synthase modulator, for the potential treatment of sepsis and hypotension. By March 1999, ONO-1714 had entered phase I trials [354023]. By June 2002, a phase II trial in hypotension during dialysis was ongoing in Japan and clinical pharmacology trials were underway in the UK [446138].

Role of bacteria and inducible nitric oxide synthase activity in the systemic inflammatory microvascular response provoked by indomethacin in the rat.

The role of bacteria and nitric oxide (NO), formed by the inducible isoform of NO synthase (iNOS), in a widespread systemic inflammatory microvascular response that follows indomethacin administration, has been investigated in the rat. Subcutaneous administration of indomethacin (10 mg kg(-1)) daily for 2 days produced an increase in microvascular leakage of radiolabelled albumin accompanied by expression of iNOS activity in the lung, liver, spleen and kidney, as well as in the jejunum, caecum, colon and ileum. Pretreatment with dexamethasone (1 mg kg(-1) day(-1), s.