Review article: the pharmacology of rabeprazole

Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H⁺,K⁺-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5–40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori , with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori . Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.     

Review article: pancreatic renin-angiotensin systems in health and disease

Aliment Pharmacol Ther 2011; 34: 840–852

Summary

Background In addition to the circulating (endocrine) renin–angiotensin system (RAS), local renin–angiotensin systems are now known to exist in diverse cells and tissues. Amongst these, pancreatic renin–angiotensin systems have recently been identified and may play roles in the physiological regulation of pancreatic function, as well as being implicated in the pathogenesis of pancreatic diseases including diabetes, pancreatitis and pancreatic cancer. Aim To review and summarise current knowledge of pancreatic renin–angiotensin systems. Methods We performed an extensive PubMed, Medline and online review of all relevant literature. Results Pancreatic RAS appear to play various roles in the regulation of pancreatic physiology and pathophysiology. Ang II may play a role in the development of pancreatic ductal adenocarcinoma, via stimulation of angiogenesis and prevention of chemotherapy toxicity, as well as in the initiation and propagation of acute pancreatitis (AP); whereas, RAS antagonism is capable of preventing new‐onset diabetes and improving glycaemic control in diabetic patients. Current evidence for the roles of pancreatic RAS is largely based upon cell and animal models, whilst definitive evidence from human studies remains lacking. Conclusions The therapeutic potential for RAS antagonism, using cheap and widely available agents, and may be untapped and such roles are worthy of active investigation in diverse pancreatic disease states.     

Review article: short chain fatty acids in health and disease

Short chain fatty acids (SCFAs) have been the subject of much research over the past few decades. They play a vital role in maintenance of colonic integrity and metabolism. They are produced when dietary fibre is fermented by colonic bacteria. SCFAs are avidly absorbed in the colon, at the same time as sodium and water absorption and bicarbonate secretion. Once absorbed, SCFAs are used preferentially as fuel for colonic epithelial cells and have trophic effects on the epithelium. Clinically, SCFAs have been studied as possible therapeutic agents in diversion colitis, ulcerative colitis, radiation proctitis, pouchitis and antibiotic-associated diarrhoea. Although some promising effects have been observed in uncontrolled studies, a specific therapeutic role for SCFAs remains to be defined. SCFAs may be the effector of the beneficial role of fibre in prevention of colon cancer.     

Review of rabeprazole in the treatment of gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) is an increasing health problem in developed countries and is associated with enormous costs in terms of reduced quality of life, loss of productivity, health expenses and mortality. The gastrointestinal disease with the highest annual direct costs in the US (in the year 2000) was GERD (9.3 billion US dollars). GERD is primarily a motility disorder of the oesophagus, however, there are no available promotility drugs on the market. The main symptoms are heartburn and acid regurgitation arising from the reflux of gastric acid, which is the only factor at present suited for pharmacological intervention. The proton pump inhibitors (PPIs) give optimal benefit in the treatment of GERD. The sales of PPIs in the year 2002 amounted to 12 billion US dollars in North America and 4 billion US dollars in Europe and the sales have been increasing by > 10% annually. This paper reviews the use of PPIs in the treatment of GERD with particular focus on one of the newer agents, rabeprazole.     

Review article: bone disease in inflammatory bowel disease

Inflammatory bowel disease (IBD) is associated with an increased incidence of osteoporosis. Osteoporosis with osteoporotic pain syndromes, fragility fractures and osteonecrosis accounts for significant morbidity and impacts negatively on the quality of life. It is generally agreed that there is a need to increase awareness for inflammatory bowel disease-associated osteoporosis. However, the best ways in which to identify at-risk patients, the epidemiology of fractures and an evidence-based rational prevention strategy remain to be established. The overall prevalence of IBD-associated osteoporosis is 15%, with higher rates seen in older and underweight subjects. The incidence of fractures is about 1 per 100 patient years, with fracture rates dramatically increasing with age. While old age is a significant risk factor, disease type (Crohn's disease or ulcerative colitis) is not related to osteoporosis risk. Corticosteroid use is a major variable influencing IBD-associated bone loss; however, it is difficult to separate the effects of corticosteroids from those of disease activity. The recommendations in inflammatory bowel disease are similar to those for postmenopausal osteoporosis, with emphasis on lifestyle modification, vitamin D (400-800 IE daily) and calcium (1000-1500 mg daily) supplementation and hormone replacement therapy (oestrogens/selective oestrogen receptor modulators in women, testosterone in hypogonadal men). Bisphosphonates have been approved for patients with osteoporosis (T-score < 2.5), osteoporotic fragility fractures and patients receiving continuous steroid medication. Data on the recently Food and Drug Administration-approved osteoanabolic substance parathyroid hormone and on osteoprotegerin are promising in terms of both steroid-induced and inflammation-mediated osteoporosis, the key elements of inflammatory bowel disease-associated bone disease.     

Review article: Crohn's disease: monitoring disease activity

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES-CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.     

Review article: cytochrome P450 and the metabolism of proton pump inhibitors — emphasis on rabeprazole

The proton pump inhibitors rabeprazole, omeprazole, lansoprazole, and pantoprazole undergo an extensive hepatic biotransformation. In the liver, they are metabolized to varying degree by several cytochrome P450 (CYP) isoenzymes which are further categorized into subfamilies of related polymorphic gene products. The principal isoenzymes involved in the metabolism of proton pump inhibitors are CYP2C19 and CYP3A4. Of these two, minor mutations in CYP2C19 affect its activity in the liver and, in turn, the metabolic and pharmacokinetic profiles of the proton pump inhibitors. The metabolism of rabeprazole is less dependent on CYP2C19 and therefore is the least affected by this genetic polymorphism. Recent studies have brought to light the important role that this polymorphism plays in the therapeutic effectiveness of proton pump inhibitors during the treatment of acid-related diseases.     

Review article: coeliac disease and its management

Coeliac disease (CD) is a disorder of the small intestine, characterized by villous atrophy, due to an intolerance to dietary gluten in genetically susceptible individuals, which responds to gluten withdrawal. The underlying immunological mechanisms causing the disorder are still being worked out.
In recent years a wide range of clinical presentations has become increasingly apparent, as has a lengthening list of associated conditions. Severe malabsorption with steatorrhoea and profound weight loss is seen infrequently, perhaps as a result of earlier diagnosis and the recognition of 'silent' and 'latent' disease.
The prevalence of CD as judged by population screening with, in particular, anti-endomysial antibodies, appears to be much higher than that found with clinically apparent cases.
There are a variety of well recognized complications, the commonest probably being osteopenia and osteoporosis. The marked increased risk of lymphoma can be avoided by a strict gluten-free diet.
Follow-up of patients needs to be lifelong with prompt investigation of new symptoms and blood test abnormalities.     

Review article: Osteoporosis and inflammatory bowel disease

Studies using dual-energy X-ray absorptiometry have suggested a high prevalence of osteoporosis in inflammatory bowel disease. However, population-based data on fracture incidence suggest only a small increased risk of fracture amongst patients with inflammatory bowel disease compared with the general population. Therefore, it would be helpful to identify patients with inflammatory bowel disease at particularly high risk for fracture so that these risks might be modified or interventions might be undertaken. The data on calcium intake as a predictor of bone mineral density are conflicting. Although there are data suggesting that a one-time survey to determine current calcium intake will not help to predict bone mineral density in inflammatory bowel disease, persistently reduced calcium intake does appear to lead to lower bone mineral density. In the general population, body mass is strongly correlated with bone mineral density, which also appears to be true in Crohn's disease. Hence, subjects with inflammatory bowel disease and considerable weight loss, or who are obviously malnourished, could be considered for bone mineral density testing, and the finding of a low bone mineral density would suggest the need for more aggressive nutritional support. Although vitamin D is undoubtedly important in bone health, vitamin D intake and serum vitamin D levels do not correlate well with bone mineral density. Sex hormone deficiency can also adversely affect bone health, although a well-developed strategy for sex hormone measurements in patients with inflammatory bowel disease remains to be established. Ultimately, the determination of genetic mutations that accurately predict fracture susceptibility may be the best hope for developing a simplified strategy for managing bone health in inflammatory bowel disease. The therapy of osteoporosis in inflammatory bowel disease has been adapted from other osteoporosis settings, such as post-menopausal or corticosteroid-induced osteoporosis. To date, there remains no therapy proven to be efficacious in inflammatory bowel disease-related osteoporosis; however, calcium and vitamin D supplementation and bisphosphonates have their roles.     

Review article: thiopurines in inflammatory bowel disease

BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.     

Review article: aminosalicylates in inflammatory bowel disease

Aminosalicylate therapy for ulcerative colitis remains a foundational strategy for the induction and maintenance of remission for mild to moderate disease. Although it seems clear that topical mesalazine (mesalamine) is the most efficacious approach to distal ulcerative colitis, recent trials with orally delivered azo conjugates suggest that there may be an advantage over pH-released mesalazine as a first-line approach to active disease. No such comparisons are available for azo products and the prolonged-release formulation, Pentasa. However, recent meta-analyses have demonstrated that, although there is little difference in systemic exposure between marketed products, luminal concentrations may vary. In maintenance therapy, aminosalicylates remain the standard approach after aminosalicylate-induced remission. A number of gaps remain in the evidence base with regard to the optimal dosing of oral mesalazine as a maintenance agent, whether oral mesalazine can maintain remissions after rectal mesalazine induction, and the dose-response and efficacy of aminosalicylates after steroid- or ciclosporin-induced remissions. Although aminosalicylates have been advocated for several decades in Crohn's disease, a number of controversies have evolved since the original trials with sulfasalazine in active Crohn's disease. The original trials demonstrated benefits for sulfasalazine in colonic involvement, but controlled trial evidence for the role of sulfasalazine as maintenance therapy has not been as firmly established. In addition, although oral mesalazine has been demonstrated in controlled trials to be superior to placebo in mild to moderate disease, it is less efficacious than corticosteroids at inducing remissions. The maintenance benefits of mesalazine appear to be limited to patients 'induced into remission' with mesalazine and in some post-operative settings.