Review article: clinical pharmacology models of irritable bowel syndrome

This review describes the basis for development of clinical pharmacology models of irritable bowel syndrome (IBS) and presents a critical analysis of current models. IBS is becoming a more circumscribed diagnosis by improved symptom criteria and this is perceived as helpful progress for the development of suitable models. Concepts about the aetiopathogenesis and pathophysiology of IBS are also evolving. Different models have been established to study specific derangements in motor function, visceral reflexes and conscious perception of gut stimuli. The review also focuses on specific examples of drug evaluation using appropriate and validated models.     

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: anti-diarrhoeal pharmacology and therapeutics

Anti-diarrhoeal drugs reduce the symptoms of diarrhoea (loose stool consistency, frequency of defecation and excessive stool weight) by effects on intestinal transit, mucosal transport or luminal contents. Opiates and opioids are the most useful anti-diarrhoeal agents. Opiates have major effects on intestinal transit; pro-absorptive and anti-secretory effects are less well documented, but may be important for some of these drugs. Alpha-adrenergic agonists, somatostatin analogues and several other agents have had limited clinical use; these drugs may modify mucosal transport in addition to slowing transit. Adsorbents, bismuth and stool texture modifiers are used frequently by the public, but their efficacy is largely unproven. Oral rehydration solutions have had the greatest impact in saving lives and continue to be improved. Many new approaches to the treatment of diarrhoea are yet to be exploited.     

Review article: safety of infliximab in clinical trials

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, contains murine protein elements and targets the immune system, raising concerns about the potential for immune sensitization and immuno-suppressive sequelae. However, long-standing inflammatory disease with high activity and chronic immunosuppressant therapy can also predispose patients to immunosuppressive sequelae. Patients with Crohn's disease, rheumatoid arthritis and other indications received single or multiple doses of infliximab and their condition was followed for up to 3 years. Adverse events, most frequently headache, nausea, and upper respiratory tract infection, were generally mild and occurred in 76% of infliximab-treated patients vs. 57% of placebo-treated recipients. Human antichimeric antibodies developed in 13% of patients, increasing the potential for subsequent infusion reactions. Antibodies to double-stranded DNA developed in a small percentage of patients. Other antinuclear antibodies characteristic of serum lupus erythematosus were not found; no patient developed a true lupus syndrome and no other autoimmune disorders were reported. Infliximab is not associated with typical immunosuppressive sequelae, such as infections and malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated, serious adverse events were infrequent, successfully managed with medication and without sequelae, and overall mortality was within the expected incidence for this patient population.     

Review article: Single subject trials as a research instrument in gastrointestinal pharmacology

The single subject trial is a randomized controlled trial carried out in the individual patient, and the result obtained is specific to the individual patient and the drug being investigated. This type of trial offers a supplement to traditional parallel group trials, especially in patients with heterogeneous disorders, often characterized by varying treatment responses and/or high placebo response rates. Pooled results from several individual single subject trials could extend the conclusions beyond the individual patient, and help to characterize a subset of responders to a specific treatment or clarify the heterogeneity of the disease. The basic principles of the different single subject trial designs are described. Advantages and limitations are reviewed with a special focus on published trials in functional gastrointestinal disorders. The single subject trial may be a valuable supplement to traditional drug treatment trials, either used as isolated trials in individual patients to determine optimal therapy, or in groups of patients to identify those with a uniform response to treatment. However, the lack of validation and reliability studies limits the value of the single subject trials presented so far.     

Review article: rabeprazole's tolerability profile in clinical trials

Rabeprazole is a new member of a class of substituted benzimidazole drugs known as proton pump inhibitors. Comparative trials have demonstrated that it is at least as effective as omeprazole for the treatment of gastro-oesophageal reflux disease (GERD), duodenal ulcers, or gastric ulcers. It is significantly more effective than histamine₂-receptor antagonists for acid suppression, GERD healing and pain relief, and duodenal ulcer healing and pain relief. Adverse events reported during clinical trials provide an important indication of a medication's tolerability. We demonstrate that rabeprazole has a favourable adverse events profile. It is well tolerated in placebo-controlled studies and comparative trials with omeprazole and H₂-receptor antagonists. Moreover, no dose adjustments are required for special populations, such as the elderly or patients with renal or mild-to-moderate hepatic disease. Adverse events data from clinical trials support the use of rabeprazole as a treatment for acid-related diseases.     

Pharmacology and clinical experience with alosetron

Alosetron (Lotronex) is a potent, highly selective 5-HT(3) antagonist. Animal models have shown it to be active in anxiety, psychosis, cognitive impairment, emesis and drug withdrawal, though its application in humans has been almost entirely restricted to irritable bowel syndrome (IBS). Alosetron does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and is widely distributed throughout tissues after oral or iv. dosing in animals. Its metabolism is rapid and extensive with N-demethylation, hydroxylation and oxidation. The drug, or its two principal metabolites, is equally excreted through the biliary tract and kidneys. Alosetron has proved safe in a range of toxicity studies; at high repeated dosing, clinical signs were transient and repeated administration produced no significant adverse effects on fertility, reproductive performance or fetal development. In pharmacokinetic studies, bioavailability of alosetron in healthy volunteers is approximately 60% and the plasma half-life is about 1.5 h. There are some gender differences in the pharmacokinetic profile, with 30 - 50% higher alosetron concentrations in females. No consistent differences in alosetron serum concentrations between the young and elderly were observed. The pharmacokinetics of single, oral doses of alosetron are linear up to 8 mg. In human pharmacodynamic studies, alosetron increased basal jejunal water and electrolyte absorption, increased colonic transit time and, consequently, whole gut transit time. Alosetron has been evaluated in two large Phase II trials (randomised, double-blinded, placebo-controlled) and in Phase III trials which included a four-week observation period after cessation. Dose response studies suggested that the effective dosages could be between 1 and 2 mg, twice-daily. In Phase II trials, alosetron, 1 mg b.i.d., resulted in a greater proportion of non-constipated IBS patients reporting adequate relief of pain and discomfort, as well as improvement of bowel symptoms, frequency, urgency and stool consistency when compared with placebo. However, this beneficial effect was seen exclusively among females. Phase III studies evaluated exclusively females with non-constipated IBS and confirmed the results of the Phase II studies. Alosetron was well-tolerated in all studies, with the most frequently recorded adverse event being constipation. Thus, alosetron appears promising in the treatment of abdominal pain and discomfort and normalising of bowel function in patients with non-constipated IBS. It also improves quality of life, has a high degree of tolerability and has an excellent safety profile to date.     

Review article: pegylated interferons: chemical and clinical differences

Pegylated interferon therapy for the treatment of chronic hepatitis C virus provides significant increases in sustained virological response rates compared with standard interferons. Two pegylated interferons are now available and are used in conjunction with ribavirin to maximize response rates in infected patients. The two pegylated interferons, peginterferonalpha-2a and peginterferonalpha-2b, differ substantially in terms of their chemical and structural characteristics, pharmacokinetic and pharmacodynamic properties, and dosing and administration. A full understanding of the differences between the two drugs is important to maximize the clinical benefits. Controlled studies designed to characterize the effects of the two drugs on viral kinetics and sustained virological response rates are emerging and may help to shed additional light on the use of these compounds in patients with chronic hepatitis C.     

Pharmacology and clinical experience with alosetron

Alosetron (Lotronex) is a potent, highly selective 5-HT₃ antagonist. Animal models have shown it to be active in anxiety, psychosis, cognitive impairment, emesis and drug withdrawal, though its application in humans has been almost entirely restricted to irritable bowel syndrome (IBS). Alosetron does not cause adverse pharmacodynamic effects, is absorbed rapidly after oral administration and is widely distributed throughout tissues after oral or iv. dosing in animals. Its metabolism is rapid and extensive with N-demethylation, hydroxylation and oxidation. The drug, or its two principal metabolites, is equally excreted through the biliary tract and kidneys. Alosetron has proved safe in a range of toxicity studies; at high repeated dosing, clinical signs were transient and repeated administration produced no significant adverse effects on fertility, reproductive performance or fetal development. In pharmacokinetic studies, bioavailability of alosetron in healthy volunteers is approximately 60% and the plasma half-life is about 1.5 h. There are some gender differences in the pharmacokinetic profile, with 30 - 50% higher alosetron concentrations in females. No consistent differences in alosetron serum concentrations between the young and elderly were observed. The pharmacokinetics of single, oral doses of alosetron are linear up to 8 mg. In human pharmacodynamic studies, alosetron increased basal jejunal water and electrolyte absorption, increased colonic transit time and, consequently, whole gut transit time. Alosetron has been evaluated in two large Phase II trials (randomised, double-blinded, placebo-controlled) and in Phase III trials which included a four-week observation period after cessation. Dose response studies suggested that the effective dosages could be between 1 and 2 mg, twice-daily. In Phase II trials, alosetron, 1 mg b.i.d., resulted in a greater proportion of non-constipated IBS patients reporting adequate relief of pain and discomfort, as well as improvement of bowel symptoms, frequency, urgency and stool consistency when compared with placebo. However, this beneficial effect was seen exclusively among females. Phase III studies evaluated exclusively females with non-constipated IBS and confirmed the results of the Phase II studies. Alosetron was well-tolerated in all studies, with the most frequently recorded adverse event being constipation. Thus, alosetron appears promising in the treatment of abdominal pain and discomfort and normalising of bowel function in patients with non-constipated IBS. It also improves quality of life, has a high degree of tolerability and has an excellent safety profile to date.     

Review article: gastro-oesophageal reflux disease--pathophysiological issues of clinical relevance

Gastro-oesophageal reflux disease is a multifactorial disorder in which the pathophysiological mechanisms are variably combined in different patients. Motor dysfunction of the lower oesophageal sphincter (LOS) and, possibly, the proximal stomach is a major cause of the increase in the number of reflux episodes. Transient LOS relaxation is the main mechanism of reflux in many patients with endoscopically negative disease, whereas a hypotensive LOS becomes relevant only in patients with oesophagitis. Alterations in primary and secondary peristalsis contribute to the increased oesophageal acid exposure by delaying clearance. The presence of a hiatus hernia, especially when voluminous and/or non-reducible, increases the number of reflux episodes by mechanically weakening the oesophago-gastric junction, and impairs oesophageal clearance. Hypersensitivity to acid is often present and contributes to the clinical manifestations of the disease, whereas oesophageal hypersensitivity, both to chemical and mechanical stimuli, plays a predominant role in a subset of patients. Increased concentrations of noxious compounds in the oesophageal refluxate may contribute to the development of anatomical lesions, but this is still a matter for debate. The clinical relevance of Helicobacter pylori infection and of mucosal defensive factors still needs to be fully elucidated.     

Review article: the clinical management of congenital chloride diarrhoea

Aliment Pharmacol Ther 31 , 477–485

Summary

Background Congenital chloride diarrhoea in a newborn is a medical emergency, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. While most of the 250 cases reported arise from Finland, Poland and Arab countries, single cases with this autosomal recessive disorder appear worldwide. Such congenital chloride diarrhoea rarity makes diagnosis difficult. Life‐long salt substitution with NaCl and KCl stabilizes fluid, electrolyte and acid‐base balance diagnosis. When properly treated, the long‐term outcome is favourable. Aim To summarize data on congenital chloride diarrhoea diagnosis, pathophysiology and treatment, and to provide guidelines for both acute and long‐term management of congenital chloride diarrhoea. Methods Data are based on MEDLINE search for ‘chloride diarrhoea’, in addition to clinical experience in the treatment of the largest known series of patients. Results Treatment of congenital chloride diarrhoea involves (i) life‐long salt substitution; (ii) management of acute dehydration and hypokalaemia during gastroenteritis or other infections; and (iii) recognition and treatment of other manifestations of the disease, such as intestinal inflammation, renal impairment and male subfertility. Conclusions This review summarizes data on congenital chloride diarrhoea and provides guidelines for treatment. After being a mostly paediatric problem, adult patients constitute a rare challenge for gastroenterologists worldwide.     

Review article: lactose intolerance in clinical practice--myths and realities

Background  Approximately 70% of the world population has hypolactasia, which often remains undiagnosed and has the potential to cause some morbidity. However, not everyone has lactose intolerance, as several nutritional and genetic factors influence tolerance.
Aims  To review current clinical practice and identify published literature on the management of lactose intolerance.
Methods  PubMed was searched using the terms lactose, lactase and diet to find original research and reviews. Relevant articles and clinical experience provided the basis for this review.
Results  Lactose is found only in mammalian milk and is hydrolysed by lactase in the small intestine. The lactase gene has recently been identified. 'Wild-type' is characterized by lactase nonpersistence, often leading to lactose intolerance. Two genetic polymorphisms responsible for persistence have been identified, with their distribution concentrated in north Europeans. Symptoms of lactose intolerance include abdominal pain, bloating, flatulence and diarrhoea. Diagnosis is most commonly by the lactose hydrogen breath test. However, most people with hypolactasia, if given appropriate advice, can tolerate some lactose-containing foods without symptoms.
Conclusion  In clinical practice, some people with lactose intolerance can consume milk and dairy foods without developing symptoms, whereas others will need lactose restriction.     

Review article: tolevamer, a novel toxin-binding polymer: overview of preclinical pharmacology and physicochemical properties

BACKGROUND: Tolevamer is a novel toxin-binding polymer that is currently being investigated in clinical trials for the treatment of patients who have Clostridium difficile-associated diarrhoea. AIMS: To summarize the results of in vitro and in vivo preclinical studies of tolevamer. In contrast to antibiotics, tolevamer binds C. difficile toxins to interrupt toxin-mediated intestinal inflammation and tissue damage, and does not demonstrate direct antimicrobial activity. METHODS: Pharmacokinetics/pharmacodynamics were studied in rats and dogs; efficacy was studied in a hamster model. RESULTS: Studies in rats and dogs indicate that tolevamer is essentially non-absorbed from the gastrointestinal tract and show that drug interactions with commonly used therapies are unlikely. Pharmacologic studies indicate that tolevamer reduces disease severity and recurrence rates in the hamster model of C. difficile-associated diarrhoea and blocks the enterotoxic effects of toxin A in rat ileum. The binding parameters calculated for the interaction of tolevamer with toxins A and B provide a reasonable physicochemical model that supports the potential clinical utility of tolevamer. CONCLUSIONS: These preclinical results are consistent with the effectiveness and safety profile of tolevamer observed in clinical studies in patients with C. difficile-associated diarrhoea.     

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.     

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.