Alimentary Pharmacology & Therapeutics

Fabrizi, F.; Lampertico, P.; Lunghi, G.; Mangano, S.; Aucella, F.; Martin, P.

doi: 10.1111/j.1365-2036.2005.02389.xpmid: 15771749

Summary A link between hepatitis C virus infection and development of diabetes mellitus has been suggested by many investigators; however, this remains controversial. The mechanisms underlying the association between hepatitis C virus and diabetes mellitus are unclear but a great majority of clinical surveys have found a significant and independent relationship between hepatitis C virus and diabetes mellitus after renal transplantation and orthotopic liver transplantation. We have systematically reviewed the scientific literature to explore the association between hepatitis C virus and diabetes mellitus in end‐stage renal disease; in addition, data on patients undergoing orthotopic liver transplantation were also analysed. The unadjusted odds ratio for developing post‐transplant diabetes mellitus in hepatitis C virus‐infected renal transplant recipients ranged between 1.58 and 16.5 across the published studies. The rate of anti‐hepatitis C virus antibody in serum was higher among dialysis patients having diabetes mellitus (odds ratio 9.9; 95% confidence interval 2.663–32.924). Patients with type‐2 diabetes‐related glomerulonephritis had the highest anti‐hepatitis C virus prevalence (19.5% (24/123) vs. 3.2% (73/2247); P < 0.001) in a large cohort of Japanese patients who underwent renal biopsy. The link between hepatitis C virus and diabetes mellitus may explain, in part, the detrimental role of hepatitis C virus on patient and graft survival after orthotopic liver transplantation and/or renal transplantation. Preliminary evidence suggests that anti‐viral therapies prior to renal transplantation and novel immunosuppressive regimens may lower the occurrence of diabetes mellitus in hepatitis C virus‐infected patients after renal transplantation. Clinical trials are under way to assess if the hepatitis C virus‐linked predisposition to new onset diabetes mellitus after renal transplantation may be reduced by newer immunosuppressive medications.

Kuiken, S. D.; Tytgat, G. N.; Boeckxstaens, G. E.

doi: 10.1111/j.1365-2036.2005.02392.xpmid: 15771750

Summary At present, the concept of visceral hypersensitivity provides the leading hypothesis regarding the generation of symptoms in functional gastrointestinal disorders. This paper discusses the current clinical evidence for drugs that have been proposed to interfere with visceral sensitivity in functional gastrointestinal disorders. Several possible pharmacological targets have been identified to reduce visceral pain and to reverse the processes underlying the persistence of visceral hypersensitivity. However, most of the available evidence comes from experimental animal models and cannot simply be extrapolated to patients with functional gastrointestinal disorders. In this review, we selected five drug classes that have been shown to exhibit visceral analgesic properties in experimental studies, and of which data were available regarding their clinical efficacy. These included opioid substances, serotonergic agents, antidepressants, somatostatin analogues and α2‐adrenergic agonists. Although clinical trials show a limited benefit, in particular for serotonergic agents, the evidence illustrating that these effects result from normalization of visceral sensation is currently lacking. Therefore, we conclude that the concept of targeting visceral hypersensitivity as a treatment for functional gastrointestinal disorders is still controversial. Future evaluations require patient selection based on the presence of visceral hypersensitivity and application of compounds that exhibit ‘true’ viscerosensory effects.

Gisbert, J. P.; García‐Buey, L.; Pajares, J. M.; Moreno‐Otero, R.

doi: 10.1111/j.1365-2036.2005.02395.xpmid: 15771751

Summary Aim: To systematically review the experience of therapeutic studies where α‐interferon with or without ribavirin was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus may induce regression of lymphoproliferative disorders. Methods: We used bibliographical searches in electronic databases and in the Cochrane Library to determine our results. Results: Sixteen studies where an anti‐viral regimen was administered to 65 hepatitis C virus‐infected patients with lymphoproliferative disorders were identified. Complete remission of the lymphoproliferative disorder was achieved in 75% of the cases. In contrast, hepatitis C virus‐negative subjects did not respond to interferon, indicating that the response in the hepatitis C virus‐infected patients is not merely due to the antiproliferative effect of interferon. Remission after HCV eradication was maintained, provided that infection did not reappear. In hepatitis C virus‐infected patients with non‐Hodgkin's lymphoma treated with corticosteroids/chemotherapy liver function tests deterioration did not occur. The addition of interferon to standard chemotherapy may decrease hepatic side‐effects of chemotherapy. Conclusions: Although it is evident that larger therapeutical trials of anti‐viral therapy are needed to determine the role of this strategy in hepatitis C virus‐infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that interferon (plus ribavirin) is an attractive therapeutic option for some hepatitis C virus‐related low‐grade lymphomas.

Kang, J. Y.

doi: 10.1111/j.1365-2036.2005.02396.xpmid: 15771752

Summary Background: Irritable bowel syndrome has been said to be less common in developing countries compared with western populations. In some case series of irritable bowel syndrome from the Indian subcontinent and Africa, the female predominance typical of western patients did not occur. Aim and Methods: A systematic review was performed on Medline, of community prevalence studies of irritable bowel syndrome, chronic constipation and chronic diarrhoea using standardized criteria, with special reference to the effect of geography and ethnicity, and the gender distribution in different countries. Results: There is a wide variation, depending in part on the criteria used and differences in diagnostic practices and health care utilization. No convincing evidence emerged of a difference between east and west. Most series, eastern or western showed a female predominance or no gender difference. Several US studies in communities and specific populations suggest that stool frequency is lower, and the prevalence of constipation higher, among Afro‐Caribbean Americans compared with white individuals. Conclusions: Community studies in multi‐racial populations are a useful way of assessing possible ethnic differences in the frequency of irritable bowel syndrome, chronic constipation and diarrhoea, and would additionally present opportunities to relate any ethnic differences to dietary and other environmental factors.

Bardou, M.; Toubouti, Y.; Benhaberou‐Brun, D.; Rahme, E.; Barkun, A. N.

doi: 10.1111/j.1365-2036.2005.02391.xpmid: 15771753

Summary Background: Recent data suggest that profound acid suppression may improve outcomes of patients in peptic ulcer bleeding. Aim: To better characterize the role of different pharmacological therapies in this population. Methods: MEDLINE was used to identify randomized trials (01/1990–04/2003) that assessed the efficacy of pharmacological treatments for patients with bleeding peptic ulcers exhibiting high‐risk stigmata (Forrest Ia–IIb). Three groups of treatment were assessed: proton‐pump inhibitors given as high‐dose bolus followed by intravenous constant infusion (40–80 mg and at least 6 mg/h), high‐dose oral proton‐pump inhibitors (at least twice the standard dosage), non‐high‐dose proton‐pump inhibitors (other proton‐pump inhibitors dosing schedules). Mixed‐effect models were used to determine rate differences between treatment and control groups. Results: Eighteen studies (1855 patients) were included. High‐dose intravenous proton‐pump inhibitors significantly reduced rebleeding (−14.6%), surgery (−5.4%) and mortality (−2.7%) compared with placebo, and rebleeding (−20.6%) compared with H2RA. Compared with placebo, high‐dose oral proton‐pump inhibitors significantly reduced only rebleeding (−11.8%), while non‐high‐dose proton‐pump inhibitor treatment significantly improved all three outcomes. Conclusions: High‐dose intravenous proton‐pump inhibitor significantly decreases ulcer rebleeding, surgery and mortality. Early data on high‐dose oral proton‐pump inhibitor suggest improved rebleeding. The non‐high‐dose proton‐pump inhibitor regimens, including a broad range of dosing, also improved outcomes, suggesting that doses inferior to those in the high‐dose intravenous proton‐pump inhibitor may be effective.

Huang, Y.‐H.; Chen, C.‐H.; Chang, T.‐T.; Chen, S.‐C.; Chiang, J.‐H.; Lee, H.‐S.; Lin, P.‐W.; Huang, G.‐T.; Sheu, J.‐C.; Tsai, H.‐M.; Lee, P.‐C.; Huo, T.‐I.; Lee, S.‐D.; Wu, J.‐C.

Verslype, C.; George, C.; Buchel, E.; Nevens, F.; Van Steenbergen, W.; Fevery, J.

doi: 10.1111/j.1365-2036.2005.02403.xpmid: 15771755

Summary Aim: To study features in older patients with autoimmune hepatitis, as this was considered mainly a disease of young females. Methods: Analysis of 28 patients diagnosed at age ≥65 years compared with 84 younger patients. Results: The incidence was similar at all age decades. The ratio M:F was 1 : 3 (≥65 years) vs. 1 : 2 (<65 years). Presenting symptoms were not different when compared with younger patients and consisted of general malaise and fatigue (36%), jaundice ± other symptoms (50%), or ascites (11%). Antinuclear antibodies (ANA) ≥ 1/80 were positive in 93%, smooth muscle antibodies (SMA) > 1/40 in 50%, anti‐liver kidney microsomes (anti‐LKM) proved always negative. Histology showed acute necrotizing hepatitis in 19%, severe interphase hepatitis in 15%, chronic hepatitis with plasmo‐lymphocytic infiltrate in 30%, cirrhosis in 29% (with active inflammation in one‐third); biopsy was refused in 11%. The elderly responded very well to low doses of methylprednisolone (≤8 mg) and azathioprine (1 mg/kg). This schedule obviates side‐effects such as infections seen with higher dosages. Conclusion: Autoimmune hepatitis has to be also looked for in the elderly with acute and chronic hepatitis. The steroid therapy should be individualized but kept at a low dose.

Gascón, I.; Pascual, S.; Plazas, J.; Sánchez, J.; Francés, R.; Más, P.; Zapater, P.; Pérez‐Mateo, M.; Such, J.

doi: 10.1111/j.1365-2036.2005.02366.xpmid: 15771756

Summary Background: Long‐term administration of norfloxacin is recommended for secondary prophylaxis of spontaneous bacterial peritonitis in cirrhosis, but it may be associated with the development of quinolone‐resistant bacteria in stools. However, these bacteria rarely cause infections. Aim: To assess bacterial adherence of either quinolone‐sensitive or ‐resistant Escherichia coli obtained from stools of cirrhotic patients, as one of the main virulence factors, and its variations when sub‐minimum inhibitory concentration of norfloxacin were added to the medium. Methods: E. coli strains were co‐cultured with oral epithelial cells obtained from patients in presence/absence of norfloxacin. Bacterial adherence was measured as percentage of cells exhibiting positive adherence and the number of bacteria attached to epithelial cells. Results: 37 sensitive and 22 resistant E. coli strains were studied. Bacterial adherence was similar in both series (78% vs. 81%, P = N.S.), and these percentages were similarly and significantly reduced when subminimum inhibitory concentration of norfloxacin was added to the culture medium (P < 0.001). Conclusions: Bacterial adherence of E. coli obtained from patients with cirrhosis is unrelated to the sensitivity/resistance to quinolones, and is similarly reduced in both cases when subminimum inhibitory concentration of norfloxacin is added to the medium.

Setchell, K. D. R.; Galzigna, L.; O'Connell, N.; Brunetti, G.; Tauschel, H.‐D.

doi: 10.1111/j.1365-2036.2005.02385.xpmid: 15771757

Summary Background: Ursodeoxycholic acid is an approved therapy for hepatobiliary disorders but in infants and children compliance is compromised because it is formulated exclusively as capsules, or tablets. Aim: To determine the pharmacokinetics and bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) with a standard capsule (Ursofalk) in a randomized, unblinded, crossover designed study of 24 healthy adults. Methods: Equivalence was based on single bolus oral plasma pharmacokinetics and biliary ursodeoxycholic acid enrichments after repeat doses. Biliary bile acid composition and hydrophobicity index were also compared. Ursodeoxycholic acid was measured in duodenal bile by high‐performance liquid chromatography and in plasma by mass spectrometry. Results: The mean percentage biliary ursodeoxycholic acid enrichment after administration of the suspension was not significantly different from that obtained with capsules (44.2 ± 11.7% vs. 46.9 ± 10.2%, respectively). The equivalence ratio was 0.94 (95% CI: 0.8–1.1), establishing bioequivalence between suspension and capsules. Both formulations reduced the biliary hydrophobicity index and no differences in bile acid composition were observed between formulations. The plasma pharmacokinetics of both formulations was similar and the tolerability of the suspension was excellent. Conclusions: A new liquid formulation of ursodeoxycholic acid suitable for paediatric patients is pharmacologically bioequivalent to capsules when given as single, or repeated oral doses.

Chisholm, J. A.; Williams, G.; Spence, E.; Parks, S.; Keating, D.; Gavin, M.; Mills, P. R.

doi: 10.1111/j.1365-2036.2005.02365.xpmid: 15771758

Summary Background: Ocular side‐effects in the form of retinal ischaemia and haemorrhages have been reported in patients undergoing standard α‐interferon therapy. Aim: To assess the ocular impact of therapy with sustained release pegylated α‐2a interferon (Pegasys) for chronic hepatitis C. Methods: Ten patients receiving Pegasys and ribavirin and 10 healthy volunteers were recruited. Patients underwent full ophthalmic investigations and multifocal electroretinogram testing at baseline, at regular intervals during treatment and post‐treatment. The multifocal electroretinogram maps retinal function. Responses were compared with sequential recordings from healthy volunteers. Results: All patients had normal clinical ophthalmic investigations at baseline. During therapy a single patient experienced central visual disturbance lasting 24 h with no prolonged ill effect. No other patient was aware of any change in vision. Fundal abnormalities appeared in five patients during treatment. The multifocal electroretinogram showed reductions in retinal function in five patients. Nine of 10 patients exhibited abnormalities on at least one multifocal electroretinogram or fundoscopic investigation. Conclusions: Subclinical retinal toxicity during anti‐viral therapy with pegylated α‐interferon and ribavirin was frequent in this study and it suggests that patients should be warned of this risk and monitored during therapy.