Review article: drug therapy for reflux oesophagitis

Gastro-oesophageal reflux disease is a common disorder and symptoms can be mild to severe. Management of the disease should be individualized. Life-style changes are important for all patients. Drug therapy is often necessary but only very few patients with severe disease need surgical treatment. The purpose of this article is to focus on drug therapy and to review the clinical trials of all the drugs used for gastro-oesophageal reflux disease. Thereafter, judged solely on the data derived from these trials, a practical approach to the management of gastro-oesophageal reflux disease is suggested.     

Review article: Targeted drug delivery in treatment of intestinal diseases

Topical therapy within the treatment of intestinal diseases presents realistic formulation challenges for targeted drug delivery. Some relevant oral formulation concepts are reviewed. The basic principles employed are, based mainly on differences in pH and metabolic activity between the different parts of the gastrointestinal tract. A successful example of targeted drug delivery within the treatment of Crohn's disease is presented. Topical therapy for the treatment of ulcerative colitis is also discussed. Physiological variations and influence of the disease and disease status present major challenges when deciding upon a suitable formulation principle.     

Review article: hypoxia and hepatic drug metabolism—clinical implications

Most major pathways of hepatic drug metabolism are dependent on oxygen. Hepatic mixed-function oxidases use oxygen directly as a substrate, while many other enzyme systems are indirectly dependent on oxygen for the generation of essential co-factors, such as NAD+ and ATP. Studies in vitro show that many of these oxygen-dependent reactions are impaired by relatively minor reductions in oxygen supply, of a magnitude likely to be encountered in vivo. Phase I metabolism by mixed-function oxidases appears to be more sensitive to hypoxia than phase II drug conjugation, although the oxygen requirements of conjugation reactions, such as glucuronidation, may be greatly enhanced by poor nutrition or fasting. Studies in humans are few, but in general they affirm the potential importance of the effects of hypoxaemic states on hepatic drug elimination. On present evidence, special care should be taken in hypoxic patients with drugs extensively metabolized by the liver, particularly those which have a low therapeutic ratio.     

Review article: endpoints used in functional dyspepsia drug therapy trials

Aliment Pharmacol Ther 2011; 33: 634–649

Summary

Background The measurement of patient‐reported outcomes (PRO) in treatment trials for functional gastrointestinal disorders is a matter of controversy. Aim To focus on instruments and endpoints that have been used to evaluate the efficacy of therapeutic agents in functional dyspepsia (FD) trials, also considering the newly defined Rome III FD criteria. Methods A Medline search was conducted to identify relevant studies pertaining to FD treatment, with particular emphasis on the studies to date which have used validated outcome measures. Results Currently available outcome measures are heterogeneous across studies. They include global binary endpoints, analogue or categorical scoring scales, uni‐ or multi‐dimensional disease specific questionnaires, global outcome evaluations and quality of life questionnaires. Across the available outcome measures, substantial heterogeneity is found, not only in the type of endpoint measure, but also in the number and types of symptoms that are considered to be part of the FD symptom complex. Especially based on content validity, none of the existing questionnaires or endpoints can be considered sufficiently validated to be recommended unequivocally as the primary outcome measure for FD trials according to the Rome III criteria. On the other hand, existing well‐validated multi‐dimensional questionnaires that include many non‐FD symptoms can be narrowed down to evaluate only the cardinal symptoms according to Rome III. Conclusions There is an urgent need to develop Rome III‐based patient‐reported outcomes for functional dyspepsia. Well‐validated multi‐dimensional questionnaires may serve as a guidance for this purpose, and could also be considered for use in ongoing clinical trials.     

Review article: monitoring for drug side-effects in inflammatory bowel disease

The side-effects suitable for monitoring in patients with inflammatory bowel disease being treated with the four main groups of drugs (5-aminosalicylic acid preparations, azathioprine and 6-mercaptopurine, methotrexate, and corticosteroids) are reviewed. On the basis of the reported frequency, severity and timing of side-effects, a practical scheme of monitoring is recommended. This includes a baseline measurement of full blood count, creatinine and liver function tests in all patients. In the absence of worrying symptoms, we recommend the following: (i) no monitoring for sulfasalazine; (ii) for other 5-aminosalicylic acid preparations, the measurement of creatinine at 6 and 12 months and then annually; (iii) for azathioprine/6-mercaptopurine, thiopurine methyltransferase genotype/phenotype determination has no role in treatment monitoring, but a full blood count at 2 weeks, 1 month, 3 months and then every 3 months should be performed; (iv) for methotrexate, a full blood count and liver function tests should be performed every 3 months; (v) for steroids, dual energy X-ray absorptiometry bone scanning should be performed at the start of therapy, every year in which steroids are used if the T score is < 0, and every 3-5 years if the T score is > 0.     

Review article: assessment of drug therapy in inflammatory bowel disease

This review article surveys the clinical and laboratory parameters used to assess and quantitate inflammation in ulcerative colitis and Crohn's disease, with particular reference to their usage in controlled trials of drugs in inflammatory bowel disease.     

Review article: mechanisms and management of hepatotoxicity in ecstasy (MDMA) and amphetamine intoxications

The social use of ecstasy (methylenedioxymethampheta-mine, MDMA) and amphetamines is widespread in the UK and Europe, and they are popularly considered as 'safe'. However, deaths have occurred and hepatotoxicity has featured in many cases of intoxication with amphetamine or its methylenedioxy analogues such as ecstasy. Recreational use of these drugs presents an important but often concealed cause of hepatitis or acute liver failure, particularly in young people. The patterns of liver damage and multiple putative mechanisms of injury are discussed. Recognition of the aetiological agent requires a high index of suspicion. Optimum management of the resultant liver damage, including the controversial role of liver transplantation for fulminant hepatic failure, is also discussed.     

Idiosyncratic drug hepatotoxicity

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.     

Review article: a drug therapy for the prevention of variceal haemorrhage

The development of varices is a major complication of cirrhosis, and variceal haemorrhage has a high mortality. There have been major advances in the primary and secondary prevention of variceal haemorrhage over the last 20 years involving endoscopic, radiological and pharmacological approaches. This review concentrates principally on drug therapy, particularly on the numerous haemodynamic studies. Many of these drugs have not been studied in clinical trials, but provide data about the underlying pathogenesis of portal hypertension. Also covered in this review are the randomized controlled trials and meta-analyses that involve a large number of patients. These trials involve relatively few drugs such as non-selective beta-blockers and nitrates. Correlations between haemodynamic and clinical parameters are discussed. Despite the recent increase in the use of alternative endoscopic therapies, an effective and well tolerated drug remains a clinically important research goal.     

Review article: the complexity of drug development for irritable bowel syndrome

Drug development for functional gastrointestinal disorders is complex. These conditions involve central and peripheral physiological changes, together with psychological factors. Methodological problems have included a poor appreciation of the physiological and psychological correlates of patients' symptoms, a lack of animal models of proven relevance, and safety issues. Government, patient pressure groups and the Internet can also influence a drug's success. Most recent interest has focused on the serotonin (5-HT) modifying drugs. Cisapride has been withdrawn in some countries because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists, developed to modify visceral sensation, have caused constipation; alosetron, also withdrawn, caused ischaemic colitis. The 5-HT4 agonists induce peristalsis; tegaserod and prucalopride, both delayed in their development due to issues of safety and efficacy, benefit patients with 'constipation-predominant' irritable bowel syndrome or idiopathic constipation. 5-HT1 agonists improve impaired gastric accommodation and symptoms in patients with functional dyspepsia. Antidepressants also affect serotonin metabolism. Previous examples of success in this area involved drugs targeted at peripheral receptors mediating motor function or secretion. Modification of sensory function is a much more challenging objective. The experience with serotonin modifying drugs has been mixed, and some important lessons are there to be learnt.     

Review article: haemochromatosis

Hereditary haemochromatosis is the prototype disease for primary iron overload. The disorder is very common, especially amongst subjects of Northern European extraction. It is characterized by an autosomal recessive mode of inheritance, and most cases are homozygous for the C282Y mutation in the HFE gene. Haemochromatosis is now recognized to be a complex genetic disease with probable significant environmental and genetic modifying factors. The early diagnosis of individuals at risk for the development of haemochromatosis is important, because survival and morbidity are improved if phlebotomy therapy is instituted before the development of cirrhosis. The cost-effectiveness and utility of large-scale screening for haemochromatosis have been questioned given that many individuals with the homozygous C282Y mutation do not have iron overload or end-organ damage. However, the use of phenotypic tests, such as serum transferrin-iron saturation, for initial screening avoids the problem of the identification of non-expressing homozygotes. Liver biopsy remains important in management to determine the presence or absence of cirrhosis, particularly amongst patients with serum ferritin levels greater than 1000 ng/mL or elevated liver enzymes. Those with non-HFE haemochromatosis who cannot be identified on genotypic testing should have a liver biopsy to establish diagnosis. Patients with end-stage liver disease may develop liver failure or primary liver cancer, and liver transplantation may be required. Liver transplantation for haemochromatosis is associated with a poorer outcome compared with other indications because of infections and cardiac complications.     

Review article: tegaserod

Tegaserod (Zelmac), an aminoguanidine indole derivative of serotonin, is a selective partial agonist highly selective for 5-HT(4) receptor with an affinity constant in the nanomolar range. Tegaserod does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and distributes widely into tissues. Pharmacokinetics of oral tegaserod are linear in the 2--12 mg dose range. After oral administration tegaserod is metabolized mainly pre-systemically; when absorbed, intact tegaserod is excreted as N-glucuronides mainly via the bile. No clinically relevant drug--drug interactions were identified. Tegaserod has proven safe in toxicity studies. In pharmacodynamic studies, tegaserod stimulated the peristaltic reflex in vitro, increased canine intestinal and colonic motility and transit, reduced visceral afferent firing or sensation in response to distension in animals, and accelerated gastric, small bowel and colonic transit in healthy patients, and small bowel transit in patients with constipation-predominant irritable bowel syndrome. Three large phase III randomized, double-blinded, and placebo-controlled trials were performed predominantly in females (approximately 85%) with constipation-predominant irritable bowel syndrome. Overall, phase III results support efficacy as assessed by the subject's global assessment of relief with significant improvement in secondary endpoints such as abdominal pain, bowel frequency and consistency. Tegaserod was well-tolerated; the most frequent adverse event was transient diarrhoea.     

Review article: gastroparesis

Background  Gastroparesis is a chronic disorder caused by stomach pump failure and characterized by profound nausea, vomiting and epigastric pain. Most often, the cause is unapparent and of the known associations, diabetes is the most common. Diagnosis is usually made using an isotope-labelled test meal. Treatment is incremental and includes education, dietary support, prokinetic and antiemetic agents. There are novel approaches including gastric neurostimulation.
Aim  To review current concepts of gastric motor function, aetiology, investigation and treatment of gastroparesis.
Methods  A systematic web-based review of the literature was undertaken using a lexicon of terms associated with gastroparesis.
Results  There are few controlled studies of this condition. Little is known about causation or underlying nerve, muscle or pacemaker pathology. Idiopathic gastroparesis occurs most commonly in women and gastric emptying is often abnormal in diabetes. Isotopic gastric scintigraphy remains the gold standard investigation, but alternative tests are being developed. Treatment is multimodal and includes education, and nutritional support. There are no adequately powered controlled trials to support a particular drug regimen. In intractable gastroparesis, gastric neurostimulation appears to offer benefit.
Conclusion  Despite a significant progress in the past decade, further controlled trials are required into the therapeutic options available for treating this intriguing condition.     

Idiosyncratic drug hepatotoxicity: a 2008 update

Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.     

Review article: orofacial granulomatosis

Orofacial granulomatosis is an uncommon clinicopathological entity describing patients who have oral lesions characterized by persistent and/or recurrent labial enlargement, oral ulcers and a variety of other orofacial features, who on lesional biopsy have lymphoedema and non-caseating granulomas. The aetiology of oral lesions with non-caseating granulomas includes oral Crohn's disease (some patients with oral lesions will develop typical bowel symptoms of Crohn's disease in ensuing months to years), tooth-associated infections, sarcoidosis and food or contact allergies. Treatment of orofacial granulomatosis is not reliably effective and may not be always necessary, although most patients do require some medical intervention.