Alimentary Pharmacology & Therapeutics

Kozuch, P. L.; Brandt, L. J.

doi: 10.1111/j.1365-2036.2005.02269.xpmid: 15691294

Summary Mesenteric ischaemia results from decreased blood flow to the bowel, causing cellular injury from lack of oxygen and nutrients. Acute mesenteric ischaemia (AMI) is an uncommon disorder with high morbidity and mortality, but outcomes are improved with prompt recognition and aggressive treatment. Five subgroups of AMI have been identified, with superior mesenteric artery embolism (SMAE) the most common. Older age and cardiovascular disease are common risk factors for AMI, excepting acute mesenteric venous thrombosis (AMVT), which affects younger patients with hypercoaguable states. AMI is characterized by sudden onset of abdominal pain; a benign abdominal exam may be observed prior to bowel infarction. Conventional angiography and more recently, computed tomography angiography, are the cornerstones of diagnosis. Correction of predisposing conditions, volume resuscitation and antibiotic treatment are standard treatments for AMI, and surgery is mandated in the setting of peritoneal signs. Intra‐arterial vasodilators are used routinely in the treatment of non‐occlusive mesenteric ischaemia (NOMI) and also are advocated in the treatment of occlusive AMI to decrease associated vasospasm. Thrombolytics have been used on a limited basis to treat occlusive AMI. A variety of agents have been studied in animal models to treat reperfusion injury, which sometimes can be more harmful than ischaemic injury. Chronic mesenteric ischaemia (CMI) usually is caused by severe obstructive atherosclerotic disease of two or more splanchnic vessels, presents with post‐prandial pain and weight loss, and is treated by either surgical revascularization or percutaneous angioplasty and stenting.

Chan, C. W.; Gunsar, F.; Feudjo, M.; Rigamonti, C.; Vlachogiannakos, J.; Carpenter, J. R.; Burroughs, A. K.

doi: 10.1111/j.1365-2036.2005.02318.xpmid: 15691295

Summary Background : It is uncertain whether ursodeoxycholic acid therapy slows down the progression of primary biliary cirrhosis, according to two meta‐analyses. However, the randomized trials evaluated had only a median of 24 months of follow‐up. Aim : To evaluate long‐term ursodeoxycholic acid therapy in primary biliary cirrhosis. Methods : We evaluated 209 consecutive primary biliary cirrhosis patients, 69 compliant with ursodeoxycholic acid and 140 untreated (mean follow‐up 5.79 (s.d. = 4.73) and 4.87 (s.d. = 5.21) years, respectively) with onset of all complications documented. Comparison was made following adjustment for baseline differences according to Cox modelling, Mayo and Royal Free prognostic models. Results : Bilirubin and alkaline phosphatase concentrations improved with ursodeoxycholic acid (at 36 months, P = 0.007 and 0.018, respectively). Unadjusted Kaplan–Meier analysis showed benefit (P = 0.028), as 44 (31%) untreated and 15 (22%) ursodeoxycholic acid patients died or had liver transplantation. However, there was no difference when adjusted by Cox modelling (P = 0.267), Mayo (P = 0.698) and Royal Free models (P = 0.559). New pruritus or fatigue or other complications were not different, either before or after adjustment for baseline characteristics. Conclusions : Long‐term ursodeoxycholic acid therapy did not alter disease progression in primary biliary cirrhosis patients despite a significant improvement in serum bilirubin and alkaline phosphatase consistent with, and similar to, those seen in ursodeoxycholic acid cohorts in randomized trials.

Dimoulios, P.; Kolios, G.; Notas, G.; Matrella, E.; Xidakis, C.; Koulentaki, M.; Tsagarakis, N.; Kouroumalis, A.; Kouroumalis, E.

doi: 10.1111/j.1365-2036.2005.02307.xpmid: 15691296

Summary Background : Endothelins and nitric oxide regulate sinusoidal blood flow and the perfusion of the peribiliary vascular plexus. Aims : To study the serum and hepatic vein concentration of ET‐1, ET‐2, ET‐3 and nitric oxide in patients with primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment. Methods : Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. Endothelins were measured with commercial enzyme‐linked immunosorbent assays and nitrites/nitrates with a modification of Griess reaction. Results : The ET‐1 and ET‐3 levels were similar in patients and controls. Primary biliary cirrhosis patients had the highest serum ET‐2 (P < 0.001) compared with other groups. Nitrites/nitrates was increased in primary biliary cirrhosis (P < 0.05) compared with normal. ET‐2 and nitric oxide were similar in all primary biliary cirrhosis stages. Ursodeoxycholic acid significantly decreased ET‐2 in all stages (I and II: P < 0.05 and III and IV: P < 0.01) and increased nitric oxide (P < 0.05) in early primary biliary cirrhosis. Hepatic vein ET‐1 and ET‐3 were higher in viral cirrhosis patients, but only in primary biliary cirrhosis a significant difference for ET‐1 and ET‐3 between hepatic and peripheral veins was found. Conclusions : Increased ET‐2 is an early defect in primary biliary cirrhosis that is significantly reduced by the ursodeoxycholic acid treatment. The possibility of a more generalized endothelial cell dysfunction in primary biliary cirrhosis requires further investigation.

Tavakoli‐Tabasi, S.; Rowan, P.; Abdul‐Latif, M.; Kunik, M. E.; El‐Serag, H. B.

doi: 10.1111/j.1365-2036.2005.02299.xpmid: 15691297

Summary Background : The frequency and determinants of receipt of antiviral therapy once a diagnosis of a mood disorder is established in hepatitis C virus (HCV)‐infected patients remains unknown. Aim : To examine the incidence and determinants of receiving antiviral therapy in HCV‐infected veterans with abnormal scores of Zung Self‐Rating Depression Scale (SDS). Methods : We systematically evaluated the presence of psychiatric disorders among HCV‐infected patients with initial referral between September 2000 and May 2002. We reviewed medical records, obtained history, and administered Zung SDS to evaluate for depressive symptoms. Patients with psychiatric disorders were referred for psychiatric evaluation. The primary outcome was the receipt of antiviral therapy during and after the initial evaluation up to December 1, 2003. The association between SDS scores and receipt of antiviral therapy was examined in a multivariate Cox proportional hazards regression. Results : A total of 424 patients completed a Zung SDS. The scores were normal in only 43% of all patients, and were impaired mildly in 25%, moderately in 23%, and severely in 9%. Zung SDS scores were significantly higher in patients who served during the Vietnam War era, participated in combat, or had lower albumin levels. At the end of the first visit, 180 (42%) had psychiatric disorders. An abnormal Zung score (>55) was the only reason for referral to psychiatry in 83 of 180 patients; and in those 78 (94%) a formal psychiatric evaluation confirmed depressive disorder. Psychiatric disorders were the sole contraindication to therapy in 145 (34%) patients in whom eligibility for antiviral therapy was achieved in 42 (29%) during a mean follow‐up duration of 27 months. Conclusions : Approximately one‐quarter of patients with psychiatric disorders may become eligible for antiviral therapy following subsequent management of these disorders. The Zung self‐screening test is an easy, valid method for detecting mood disorders in HCV‐infected veterans.

Klingenstein, G.; Levy, R. N.; Kornbluth, A.; Shah, A. K.; Present, D. H.

doi: 10.1111/j.1365-2036.2005.02231.xpmid: 15691298

Summary Background : Osteonecrosis is a major complication of inflammatory bowel disease usually associated with steroid use. There are few large series available detailing the specifics of affected patients. Aim : To identify any specific characteristics of osteonecrosis in this cohort. A major focus was placed on steroid dose, the average time between diagnosis of IBD and appearance of osteonecrosis and the frequency of multiple joint involvement. Methods : Our study identified 23 patients in the practices of five gastroenterologists at the Mount Sinai Medical Center. We retrospectively reviewed their clinical history, as well as imaging studies. We classified osteonecrosis according to the Association Research Circulation Osseous (ARCO) staging system. Results : Although our prednisone dosing data could not be used as an accurate predictor of onset or joint distribution, there was a tendency for correlation between the average daily dosing and the ARCO score. The ARCO scoring system was consistent for patients with bilateral hip involvement. The distribution of affected joints in IBD is similar to other conditions associated with osteonecrosis, with hips being the most frequently involved joints. Data showed bilateral involvement in most hips, but usually unilateral disease in the shoulders and knees. Treatment options include core decompression for early stages, whereas joint replacement surgery is required for stages 3 and 4. Conclusion : IBD predisposes patients to corticosteroid induced osteonecrosis. An exact threshold dose has not been determined. The data suggests that either long term therapy or short term high dose treatment increases the risk of osteonecrosis. Even if symptoms are limited to one joint, multiple joints are often involved and comprehensive testing with MRI is indicated in all cases.

Shen, C.; Assche, G. V.; Colpaert, S.; Maerten, P.; Geboes, K.; Rutgeerts, P.; Ceuppens, J. L.

doi: 10.1111/j.1365-2036.2005.02309.xpmid: 15691299

Summary Background : Adalimumab, a fully human monoclonal antibody to tumour necrosis factor, was recently introduced for therapy of Crohn's disease. Aim : Since induction of apoptosis of inflammatory cells is thought to be an important mechanism of action of the antitumour necrosis factor monoclonal antibody infliximab, we studied the induction of apoptosis of activated peripheral blood monocytes by adalimumab. Method : Apoptosis was analysed at the levels of the cell membrane, mitochondria and DNA by flow cytometry. Results: We found that both adalimumab and infliximab induced apoptosis in cultured monocytes, while etanercept did not. Apoptosis induction was caspase‐dependent and detectable already after 2 h. The production of interleukin‐10 and interleukin‐12 by monocytes was down‐regulated significantly by adalimumab and infliximab but not by etanercept, while levels of soluble tumour necrosis factor in monocyte cultures were down‐regulated by all three reagents. Conclusions : These data show that both adalimumab and infliximab affect monocyte cytokine production and induce apoptosis of activated monocytes. Our findings will have to be further correlated to therapeutic efficacy of these antitumour necrosis factor reagents.

Fritz, E.; Hammer, H. F.; Lipp, R. W.; Högenauer, C.; Stauber, R.; Hammer, J.

doi: 10.1111/j.1365-2036.2005.02244.xpmid: 15691300

Summary Background : The effects of lactulose and polyethylene glycol on colonic transit are poorly established. Aim: To assess the effects of these laxatives on colonic transit in normal subjects. Methods : Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3‐day ingestion of 67–134 g/day lactulose, or 59 g/day polyethylene glycol. Results : At similar stool weight (lactulose: 653 ± 120 g/day; polyethylene glycol: 522 ± 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose – 403 ± 55 min; polyethylene glycol – 160 ± 41.9 min). Short chain fatty acid concentration in 24‐h stool correlated significantly with counts remaining in the distal colon at 12 h(r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = −0.56) and distal colon (r = −0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P < 0.001). Conclusion : Lactulose accelerates colonic transit. However, compared with polyethylene glycol, transit during lactulose is prolonged.

Diav‐Citrin, O.; Arnon, J.; Shechtman, S.; Schaefer, C.; Tonningen, M. R.; Clementi, M.; Santis, M.; Robert‐Gnansia, E.; Valti, E.; Malm, H.; Ornoy, A.

doi: 10.1111/j.1365-2036.2005.02306.xpmid:

Pajala, M.; Heikkinen, M.; Hintikka, J.

doi: 10.1111/j.1365-2036.2005.02296.xpmid: 15691302

Summary Background : It has been argued that patients with functional gastrointestinal disorders have mental disorders more often than healthy controls and patients with organic disease. Most studies surveying psychological factors at the population level have relied on symptom questionnaires to diagnose functional dyspepsia. However, the symptom patterns alone are unable to adequately discriminate organic from functional dyspepsia. Aim : To evaluate the frequency of mental distress in primary care patients with organic or functional dyspepsia and compare the findings with a sample of the Finnish general population. Methods : Four‐hundred consecutive, unselected dyspeptic patients were referred for upper gastrointestinal endoscopy and other diagnostic examinations. All patients compiled a self‐administered questionnaire including the 12‐item General Health Questionnaire to detect cases of recent mental disorders. Results : The prevalence of mental distress among patients with functional and organic dyspepsia was 38 and 36.4% respectively. The sex‐ and age‐adjusted risk of having mental distress was nearly fourfold higher among patients with dyspepsia than in the general population. Conclusion : Mental distress is common among patients with functional or organic dyspepsia. Nevertheless, there is no difference between patients with functional or organic dyspepsia in the prevalence or risk of mental distress.

Sheu, B.‐S.; Kao, A.‐W.; Cheng, H.‐C.; Hunag, S.‐F.; Chen, T.‐W.; Lu, C.‐C.; Wu, J.‐J.

doi: 10.1111/j.1365-2036.2005.02281.xpmid: 15691303

Summary Aim : To determine whether an increased dosage of esomeprazole 40 mg twice daily in triple therapy improved the Helicobacter pylori eradication rate for patients with different genotypes of S‐mephenytoin 4′‐hydroxylase (CYP2C19). Methods : Two hundred H. pylori‐infected dyspeptic patients were randomized to receive clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily plus either omeprazole 20 mg or esomeprazole 40 mg twice daily for 1 week. Six weeks later, the success of H. pylori eradication was defined. The genotyping of CYP2C19 in each patient was defined as homologous, heterologous extensive metabolizer or poor metabolizer. Results : The age, gender, drug compliance and proportion of CYP2C19 genotypes were similar between the two groups. The H. pylori eradication rates were also similar between the omeprazole group and the esomeprazole group (intention‐to‐treat analysis: 79% vs. 86%, P > 0.05; per‐protocol analysis: 85% vs. 94%, P > 0.05). For patients classified as homologous extensive metabolizers, the per‐protocol H. pylori eradication rate was significantly higher in the esomeprazole group than in the omeprazole group (93% vs. 76%, P < 0.05). Conclusion : Esomeprazole 40 mg twice daily for triple therapy may improve the H. pylori eradication compared to omeprazole‐based therapy, but only for homologous extensive metabolizers of CYP2C19.