bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical trial: alvimopan for the management of post‐operative ileus after abdominal surgery: results of an international randomized, double‐blind, multicentre, placebo‐controlled clinical study
Authors: BÜCHLER M. W. , SEILER C. M. , MONSON J. R. T. , FLAMANT Y. , THOMPSON‐FAWCETT M. W. , BYRNE M. M. , MORTENSEN E. R. , ALTMAN J. F. B. , WILLIAMSON R.
Published: October 2008

Aliment Pharmacol Ther 28, 312–325

Background  Post‐operative ileus (POI) affects most patients undergoing abdominal surgery.

Aim  To evaluate the effect of alvimopan, a peripherally acting mu‐opioid receptor antagonist, on POI by negating the impact of opioids on gastrointestinal (GI) motility without affecting analgesia in patients outside North America.

Methods  Adult subjects undergoing open abdominal surgery (n = 911) randomly received oral alvimopan 6 or 12 mg, or placebo, 2 h before, and twice daily following surgery. Opioids were administered as intravenous patient‐controlled analgesia (PCA) or bolus injection. Time to recovery of GI function was assessed principally using composite endpoints in subjects undergoing bowel resection (n = 738).

Results  A nonsignificant reduction in mean time to tolerate solid food and either first flatus or bowel movement (primary endpoint) was observed for both alvimopan 6 and 12 mg; 8.5 h (95% CI: 0.9, 16.0) and 4.8 h (95% CI: −3.2, 12.8), respectively. However, an exploratory post hoc analysis showed that alvimopan was more effective in the PCA (n = 317) group than in the non‐PCA (n = 318) group. Alvimopan was well tolerated and did not reverse analgesia.

Conclusion  Although the significant clinical effect of alvimopan on reducing POI observed in previous trials was not reproduced, this trial suggests potential benefit in bowel resection patients who received PCA.
Clinical trial: percutaneous acetic acid injection vs. percutaneous ethanol injection for small hepatocellular carcinoma – a long‐term follow‐up study
Authors: TSAI W.‐L. , CHENG J.‐S. , LAI K.‐H. , LIN C.‐P. , LO G.‐H. , HSU P.‐I. , YU H.‐C. , LIN C.‐K. , CHAN H.‐H. , CHEN W.‐C. , CHEN T.‐A. , LI W.‐L. , LIANG H.‐L.
Published: October 2008

Aliment Pharmacol Ther 28, 304–311

Background  The long‐term outcome of percutaneous acetic acid injection (PAI) and percutaneous ethanol injection (PEI) for treating small hepatocellular carcinoma (HCC) remains unclear.

Aim  To compare the long‐term outcome of PAI vs. PEI for treating small HCC.

Methods  From July 1998 to July 2004, 125 patients with small HCC were enrolled. Seventy patients receiving PAI and 55 patients receiving PEI were enrolled. There were no significant differences in the clinical characteristics between the two groups. Tumour recurrence and survival rates were assessed.

Results  Mean follow‐up time was 43 months. The local recurrence rate and new tumour recurrence rate were similar between the PAI and PEI groups. The PAI group had significantly better survival than the PEI group (P = 0.027). Multivariate analysis revealed that PAI was the significant factor associated with overall survival [PAI vs. PEI, RR: 0.639, 95% CI: (0.419–1.975), P = 0.038]. The treatment sessions required to achieve complete tumour necrosis were significantly fewer in the PAI group than in the PEI group (2.4 ± 1.0 vs. 2.9 ± 1.3, P = 0.018).

Conclusion  Percutaneous acetic acid injection required fewer treatment sessions than PEI and provided better survival after long‐term follow‐up.
Biliary events and an increased risk of new onset irritable bowel syndrome: a population‐based cohort study
Authors: MCNALLY M. A. , LOCKE G. R. , ZINSMEISTER A. R. , SCHLECK C. D. , PETERSON J. , TALLEY N. J.
Published: October 2008

Aliment Pharmacol Ther 28, 334–343

Background  Prospective data are lacking to determine if irritable bowel syndrome (IBS) is a risk factor for cholecystectomy, or if biliary disease and cholecystectomy predisposes to the development of IBS.

Aim  To test the hypothesis that IBS and biliary tract disease are associated.

Methods  Validated symptom surveys sent to cohorts of Olmsted County, MN, (1988–1994) with follow‐up in 2003. Medical histories were reviewed to determine any ‘biliary events’ (defined by gallstones or cholecystectomy). Analyses examined were: (i) time to a biliary event post‐initial survey and separately and (ii) risk of IBS (Rome II) in those with vs. without a prior biliary event.

Results  A total of 1908 eligible subjects were mailed a follow‐up survey. For analysis (i) of the 726 without IBS at initial survey, 44 (6.1%) had biliary events during follow up, in contrast to 5 of 93 (5.4%) with IBS at initial survey (HR 0.8, 95% CI 0.3–2.1). For analysis (ii) of the 59 subjects with a biliary event at initial survey, 10 (17%) reported new IBS on the follow‐up survey, while in 682 without a biliary event up to 1.5 years prior to the second survey, 58 (8.5%) reported IBS on follow‐up (OR = 2.2, 95% CI 1.1–4.6, P = 0.03).

Conclusion  There is an increased risk of new IBS in community subjects who have been diagnosed as having a biliary event.
Review article: panitumumab ‐ a fully human anti‐EGFR monoclonal antibody for treatment of metastatic colorectal cancer
Authors: PEETERS M. , BALFOUR J. , ARNOLD D.
Published: October 2008

Aliment Pharmacol Ther 28, 269–281

Background  Panitumumab is a fully human monoclonal IgG2 antibody targeting the epidermal growth factor receptor (EGFR).

Aim  To review the efficacy of panitumumab in the treatment of metastatic colorectal cancer (mCRC).

Methods  Available literature identified from PubMed and conference websites was reviewed.

Results  In phase 2–3 studies, panitumumab monotherapy achieved objective response rates (ORRs) of 8–13% in relapsed/refractory EGFR‐expressing mCRC. In a randomized phase 3 study (463 patients), panitumumab almost halved the risk of disease progression/death vs. a control group receiving only best supportive care (hazard ratio 0.54; 95% CI: 0.44–0.66; P < 0.0001). Objective response was achieved in 22/231 (10%) patients randomized to panitumumab – and also in 20/176 (11%) patients assigned to the control group who received panitumumab in a separate crossover protocol after disease progression. Response was confined to patients with tumours harbouring wild‐type KRAS (ORR ≈20%). Panitumumab is also being evaluated in earlier lines of treatment. Panitumumab monotherapy is generally well tolerated; the most common toxicities are skin toxicity (≈90%) and diarrhoea (<30%). Development of anti‐panitumumab antibodies (0.3% by ELISA) and grade 3–4 infusion reactions (<1%) are rare.

Conclusion  Panitumumab is an effective monotherapy option for patients with relapsed/refractory EGFR‐expressing mCRC harbouring wild‐type KRAS.
Hepatitis C patients’ self‐reported adherence to treatment with pegylated interferon and ribavirin
Authors: WEISS J. J. , BHATTI L. , DIETERICH D. T. , EDLIN B. R. , FISHBEIN D. A. , GOETZ M. B. , YU K. , WAGNER G. J.
Published: October 2008

Aliment Pharmacol Ther 28, 289–293

Background  Prior research on adherence to hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients’ dose‐taking adherence.

Aims  To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose‐taking adherence in clinic settings.

Methods  One hundred and eighty patients on treatment for hepatitis C (23% co‐infected with HIV) completed a cross‐sectional survey at the site of their hepatitis C care.

Results  Seven per cent of patients reported missing at least one injection of pegylated interferon in the last 4 weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose‐taking adherence was not associated with HCV viral load.

Conclusions  Self‐reported dose non‐adherence to hepatitis C treatment occurs frequently. Further studies of dose non‐adherence (assessed by method other than self‐report) and its relationship to HCV virological outcome are warranted.
Bleeding ectopic varices in cirrhosis: the role of transjugular intrahepatic portosystemic stent shunts
Authors: KOCHAR N. , TRIPATHI D. , MCAVOY N. C. , IRELAND H. , REDHEAD D. N. , HAYES P. C.
Published: October 2008

Aliment Pharmacol Ther 28, 294–303

Background  Bleeding from ectopic varices is uncommon but can be difficult to manage.

Aim  To report our experience of the use of transjugular intrahepatic portosystemic stent shunts (TIPSS) in the management of uncontrolled bleeding from ectopic varices.

Methods  A retrospective study of patients who had TIPSS for bleeding ectopic varices. Patients were selected from a dedicated data base.

Results  Over 14 years, of 750 TIPSS insertions, 28 patients had TIPSS for bleeding ectopic varices (Child–Pugh score: 8.8 ± 1.8). Varices were rectal (12), stomal (8), duodenal (4) and at other sites (4). Concomitant variceal embolization was performed in five. Portal pressure gradient fell from 18.2 ± 6.4 to 7.2 ± 3.5 mmHg. TIPSS achieved haemostasis in six of nine patients who presented with active bleeding. Five patients rebled from ectopic varices. This was related to shunt dysfunction in two and responded to shunt interventions. Three patients rebled despite a functional shunt. Of these, thrombin controlled bleeding in one. Eight patients developed hepatic encephalopathy post‐TIPSS.

Conclusions  Transjugular intrahepatic portosystemic stent shunt is a safe and effective treatment for bleeding ectopic varices. Rebleeding from ectopic varices related to shunt dysfunction responds to shunt intervention. A significant proportion of patients have rebleeding despite a patent shunt, when other adjunctive measures like thrombin injection may be tried.
Radioimmunological detection of anti‐transglutaminase autoantibodies in human saliva: a useful test to monitor coeliac disease follow‐up
Authors: BONAMICO M. , NENNA R. , LUPARIA R. P. L. , PERRICONE C. , MONTUORI M. , LUCANTONI F. , CASTRONOVO A. , MURA S. , TURCHETTI A. , STRAPPINI P. , TIBERTI C.
Published: October 2008

Aliment Pharmacol Ther 28, 364–370

Background  Serum radioimmunoassay (RIA) tissue transglutaminase autoantibodies (tTG‐Abs) proved to be a sensitive test also during coeliac disease (CD) follow‐up. We demonstrated that RIA tTG‐Abs could be detected in human saliva.

Aim  To evaluate salivary RIA tTG‐Abs in coeliac children on gluten‐free diet (GFD).

Methods  Saliva and serum samples from 109 coeliac children were evaluated at diagnosis (group 1: 71 females, median age 9.4 years) and 58 of them on GFD: 36 after 3–6 months (group 2a), 34 at 9 months or more (group 2b). Two gender‐ and age‐matched control groups: 89 gastroenterological patients (group 3) and 49 healthy subjects (group 4) participated in the study. Saliva and serum tTG‐Abs were detected by RIA and compared with serum tTG‐Abs ELISA and IgA anti‐endomysium antibodies (EMA).

Results  Salivary RIA tTG‐Abs were found in 94.5%, 66.7% and 50.0% of groups 1, 2a and 2b CD patients and in 98.2%, 72.2% and 50.0% of corresponding serum samples, respectively. tTG‐Abs decreased with GFD progression and a correlation was found between saliva and serum titres (r = 0.75, P = 0.0001). During the CD follow‐up, salivary and serum RIA sensitivities were comparable, and higher with respect to EMA and ELISA.

Conclusions  This study demonstrates that it is possible to detect salivary tTG‐Abs with high sensitivity not only at CD diagnosis, but also during GFD.
Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5‐HT3 receptor antagonist: a pilot study
Authors: JARCHO J. M. , CHANG L. , BERMAN S. M. , SUYENOBU B. , NALIBOFF B. D. , LIEBERMAN M. D. , AMEEN V. Z. , MANDELKERN M. A. , MAYER E. A.
Published: October 2008

Aliment Pharmacol Ther 28, 344–352

Background  Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50–70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5‐HT3R antagonist alosetron is correlated with reduced amygdala activity.

Aim  To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron.

Methods  Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment.

Results  Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre‐treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala.

Conclusions  Irritable bowel disease symptom improvement with 5‐HT3R antagonist alosetron is related to pre‐treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.
Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long‐term outcome and survival
Authors: AL‐CHALABI T. , PORTMANN B. C. , BERNAL W. , MCFARLANE I. G. , HENEGHAN M. A.
Published: October 2008

Background  Primary sclerosing cholangitis/autoimmune hepatitis (PSC/AIH) and primary biliary cirrhosis/AIH (PBC/AIH) overlap syndromes are poorly defined variants of AIH. Few large patient series exist, and there are little data on long‐term outcomes.

Aim  To compare presentation, clinical course and outcome of patients with PSC/AIH and PBC/AIH, with patients with definite AIH.

Methods  Two hundred and thirty‐eight AIH patients were compared with 10 PBC/AIH patients and 16 PSC/AIH patients presenting consecutively between 1971 and 2005 at a single centre.

Results  Autoimmune hepatitis patients were significantly more likely to present with jaundice (69.4% vs. 25%; P = 0.0145) than PBC/AIH patients. Median serum aspartate aminotransferase activity at presentation was higher in AIH patients compared with PBC/AIH and PSC/AIH patients respectively (620 vs. 94 vs. 224 IU/L; P < 0.05). PBC/AIH patients demonstrated no response to standard AIH therapy more frequently than AIH patients (25% vs. 0.8%; P = 0.0057). Significant reduction in survival was identified between patients with PSC/AIH and those without (hazard ratio: PSC/AIH vs. AIH = 2.08, PSC/AIH vs. PBC/AIH = 2.14; P = 0.039).

Conclusions  Patients with PSC/AIH have severe disease and significantly worse prognosis than patients with AIH or PBC/AIH. Recognition and close follow‐up of this cohort are warranted.
Clinical trial: insulin‐sensitizing agents may reduce consequences of insulin resistance in individuals with non‐alcoholic steatohepatitis
Authors: IDILMAN R. , MIZRAK D. , CORAPCIOGLU D. , BEKTAS M. , DOGANAY B. , SAYKI M. , COBAN S. , ERDEN E. , SOYKAN I. , EMRAL R. , UYSAL A. R. , OZDEN A.
Published: October 2008

Background  Currently, although only a few therapies normalize the liver test abnormalities with/without improving the liver histology, no pharmacologic therapy has proved to be effective for the treatment of non‐alcoholic steatohepatitis.

Aim  To investigate the role of insulin sensitizers in the treatment of individuals with non‐alcoholic steatohepatitis (NASH).

Methods  A total of 74 individuals with NASH (male/female, 44/30; mean age, 47.2 ± 9.0 years) were enrolled. Participants were divided into two distinct groups: group 1 (n = 25) participants were administered a conventional diet and exercise programme while those in group 2 (n = 49) were administered the diet and exercise programme plus insulin sensitizers.

Results  With respect to baseline metabolic, biochemical and histological parameters, no significant differences were observed between the two groups (P > 0.05). Insulin sensitizers significantly improved metabolic parameters (homeostasis model assessment‐insulin resistance score, P < 0.05), serum aminotransferase levels [aspartate aminotransferase (AST): 45.9 ± 24.2 to 33.3 ± 17.7 IU/L, P < 0.01; alanine aminotransferase (ALT): 78.2 ± 46.3 to 47.3 ± 34.5 IU/L, P < 0.001] and histological features (median non‐alcoholic fatty liver disease activity score: 5.0–3.0, P = 0.01), while diet and exercise improved serum aminotransferase levels (AST: 39.3 ± 11.1 to 30.0 ± 8.6 IU/L, P < 0.01; ALT: 66.9 ± 28.9 to 42.0 ± 16.2 IU/L, P < 0.001) at the end of the 48 weeks when compared to baseline. Insulin sensitizers improved the high‐sensitivity C‐reactive protein levels (P < 0.01). No serious adverse effects of insulin sensitizers were observed.

Conclusion  Insulin sensitizers can lead to improvement in metabolic, biochemical and histological abnormalities of NASH as a result of improved insulin sensitivity.
Predictable prolonged suppression of gastric acidity with a novel proton pump inhibitor, AGN 201904‐Z
Authors: HUNT R. H. , ARMSTRONG D. , YAGHOOBI M. , JAMES C. , CHEN Y. , LEONARD J. , SHIN J. M. , LEE E. , TANG‐LIU D. , SACHS G.
Published: October 2008

Background  AGN 201904‐Z is a new, slowly absorbed, acid‐stable pro‐proton pump inhibitor (pro‐PPI) rapidly converted to omeprazole in the systemic circulation giving a prolonged residence time.

Aim  To investigate pharmacodynamics and pharmacokinetics of AGN 201904‐Z compared to esomeprazole.

Methods  A randomized, open‐label, parallel group, investigator‐blinded intragastric pH study was conducted in 24 healthy Helicobacter pylori negative male volunteers. AGN 201904‐Z enteric‐coated capsules (600 mg/day) or esomeprazole delayed‐release tablets (40 mg/day) were administered for 5 days. Twenty‐four‐hour intragastric pH recordings were acquired at baseline, days 1, 3 and 5 with blood levels of omeprazole, AGN 201904‐Z and gastrin.

Results  On day 1, median nocturnal pH and proportion of nocturnal time with pH ≥4 and 24‐h and nocturnal time pH ≥5 were significantly higher with AGN 201904‐Z than esomeprazole. At day 5, 24‐h and median nocturnal pH were significantly higher for AGN 201904‐Z than esomeprazole (P < 0.0001). There was also a marked reduction in periods of nocturnal pH <4.0. Area under curve of the AGN 201904‐Z active metabolite (omeprazole) in the blood was twice that of esomeprazole at day 5.

Conclusions  AGN 201904‐Z produced a significantly greater and more prolonged acid suppression than esomeprazole, and nocturnal acid suppression was more prolonged over all 5 days. AGN 201904‐Z should provide true once‐a‐day treatment and better clinical efficacy than current PPIs.
Clinical trial: single‐ and multiple‐dose pharmacokinetics of polyethylene glycol (PEG‐3350) in healthy young and elderly subjects
Authors: PELHAM R. W. , NIX L. C. , CHAVIRA R. E. , CLEVELAND M. VB. , STETSON P.
Published: October 2008

Background  The pharmacokinetics of polyethylene glycol 3350 (PEG‐3350) have not been fully described because of lack of a sufficiently sensitive analytical method.

Aim  To describe the pharmacokinetics of PEG‐3350 in humans.

Methods  A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG‐3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 μg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers.

Results  Peak PEG‐3350 plasma concentrations occurred at 2–4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half‐life of about 4–6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG‐3350. Mean faecal excretion of the administered dose was 93% in young subjects.

Conclusions  For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG‐3350 in humans. These studies confirmed that orally administered PEG‐3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.
Comparison of the enteral and intravenous lansoprazole pharmacodynamic responses in critically ill patients
Authors: OLSEN K. M. , DEVLIN J. W.
Published: October 2008

Aliment Pharmacol Ther 28, 326–333

Background  While proton pump inhibitors are frequently administered in the intensive care unit, the pharmacodynamic response of acid suppression between the enteral and intravenous (IV) route is unknown.

Aim  To compare the pharmacodynamic response between enteral and IV lansoprazole in intensive care unit patients requiring stress ulcer prophylaxis therapy.

Methods  Adult mechanically ventilated patients were randomized to receive 72 h of daily enteral [lansoprazole oral disintegrating tablet (LODT) 30 mg mixed in 10 mL of water via a nasal gastric tube] or IV lansoprazole (30 mg over 30 min) therapy. Serial blood samples were collected after the first and third dose and analysed for pharmacokinetic parameters. Pharmacodynamic determination of intragastric pHmetry began prior to the first dose and continued for 72 h using a single channel pH micro‐electrode.

Results  Nineteen intensive care unit patients were randomized [LODT (n = 10); IV‐L (n = 9)]. LODT bioavailability was 76%. LODT maintained gastric pH > 4 longer than IV‐L at both 24 h (7.4 vs. 5.9 h; P = 0.039) and 72 h (10.4 and 8.9 h; P = 0.046) and resulted in a greater average pH over the first 24 h (3.67 vs. 2.89; P = 0.03).

Conclusion  Despite a lower bioavailability, enteral lansoprazole suppresses acid in intensive care unit patients to a greater extent than IV lansoprazole.
Review article: the modern management of portal hypertension – primary and secondary prophylaxis of variceal bleeding in cirrhotic patients
Authors: GARCIA‐PAGAN J. C. , DE GOTTARDI A. , BOSCH J.
Published: October 2008

Background  Variceal bleeding is a life–threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first bleeding or rebleeding is mandatory.

Aim  To provide an overview of the current knowledge on the best evidence‐based therapeutic options to prevent first or recurrent bleeding from oesophageal varices in patients with cirrhosis.

Methods  For the preparation of this narrative review, we sought to analyse randomized controlled trials that examined the efficacy and side effects of pharmacological or endoscopic therapy for the primary and secondary prophylaxis of oesophageal variceal bleeding.

Results  Endoscopic band ligation (EBL) and nonselective β‐blockers are both effective in preventing first bleeding. Until more long‐term data are available, nonselective β‐blockers should be the first treatment option because of less severe side effects. EBL is an alternative when β‐blockers are contraindicated or not tolerated. Patient preference may also be considered. For prevention of rebleeding, nonselective β‐blockers (preferably in association with isosorbide‐5‐mononitrate) or EBL are both effective and good alternative treatments. A combination of both treatments may be the best alternative.

Conclusions  A great improvement in the prevention of variceal bleeding has emerged over the last years. However, further therapeutic options that combine higher efficacy, better tolerance and fewer side effects are needed.
Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome
Authors: MANGEL A. W. , BORNSTEIN J. D. , HAMM L. R. , BUDA J. , WANG J. , IRISH W. , URSO D.
Published: October 2008

Background  In models of irritable bowel syndrome (IBS), asimadoline, a kappa‐opioid agonist, improves pain and abnormal bowel function.

Aim  To evaluate the effects of three doses of asimadoline and placebo in subjects with IBS through a double‐blind, randomized, placebo‐controlled trial.

Methods  Patients were randomly assigned to receive asimadoline 0.15, 0.5, 1.0 mg or placebo BID for 12 weeks. The primary efficacy measure was number of months of adequate relief of IBS pain or discomfort, with a prospective plan to evaluate adequate relief data by entry baseline pain and subtype. Several other endpoints were also evaluated.

Results  Five hundred and ninety‐six patients were randomized. In the ITT population, statistically significant improvement on the primary endpoint was not seen. However, in diarrhoea‐predominant IBS patients with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on total number of months with adequate relief of IBS pain or discomfort (46.7% vs. 20.0%), adequate relief of IBS symptoms (46.7% vs. 23.0%), pain scores (week 12: −1.6 vs. −0.7), pain free days (42.9% vs. 18.0%), urgency and stool frequency (−2.3 vs. −0.3). In patients with alternating IBS, significant improvement was seen on adequate relief endpoints. Asimadoline was well tolerated.

Conclusion  Asimadoline warrants further evaluation as a treatment for IBS.
Review article: current antiviral therapy of chronic hepatitis B
Authors: AYOUB W. S. , KEEFFE E. B.
Published: October 2008

Background  The long‐term goals of therapy for chronic hepatitis B are to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma.

Aim  To review the current treatment of chronic hepatitis B, with a focus on diagnosis and management of resistance and active management of suboptimal responses.

Methods  A systematic review of the literature, with a focus on recent guidelines, was undertaken.

Results  Among the six drugs licensed for the treatment of chronic hepatitis B in the US, the preferred agents in 2008 will include entecavir, peginterferon alfa‐2a, possibly telbivudine, and tenofovir following licensure. When using an oral agent, a major focus of management is on the selection of a drug with high potency and low rate of resistance, and active on‐treatment management to optimize therapy. Preventing the sequelae of antiviral drug resistance and appropriate management when resistance is initially detected are also the major focus of current management. The addition of an antiviral agent that is not cross‐resistant is critical to restore suppression of viral replication.

Conclusions  Newer agents and modified treatment strategies, especially using combination therapy, hold promise to optimize the management of patients with chronic hepatitis B by achieving the high potency and the lowest rate of resistance.
Comparative effectiveness of azathioprine in Crohn’s disease and ulcerative colitis: prospective, long‐term, follow‐up study of 394 patients
Authors: GISBERT J. P. , NIÑO P. , CARA C. , RODRIGO L.
Published: October 2008

Background The long‐term efficiacy for thiopurinic drugs in Crohn’s disease (CD), and particularly in ulcerative colitis (UC), has been insufficiently studied.

Aim To evaluate prospectively and compare the long‐term effectiveness of azathioprine (AZA) in CD and UC.

Methods Three hundred and ninety‐four AZA treated patients were included consecutively included. Truelove‐modified index and CDAI were used to assess effectiveness. Hospitalizations and surgical procedures were recorded.

Results Two hundred and thirty‐eight patients with CD and 156 with UC received AZA for a median of 38 months. Effectiveness: Partial response/remission was achieved in 34%/49% of CD patients and in 47%/42% of UC (nonstatistically significant differences). Steroid treatment: Prior to AZA, 49% of CD patients were receiving steroids, whereas only 8% needed steroids after therapy (P < 0.001). Corresponding figures in UC patients were 39% vs. 9% (P < 0.001). Hospitalizations: Prior to AZA, the rate of hospitalizations in CD was 0.190 per‐patient‐year, while after treatment, it decreased to 0.099 (P < 0.001). Corresponding hospitalization rates in UC were 0.108 vs. 0.038 (P < 0.001). Surgery: The rate of surgery in CD prior/after AZA was 0.038/0.011 per‐patient‐year (P < 0.001). The number of surgical interventions in UC prior/after AZA treatment was 26/0 (the rate per‐patient‐year was 0.018/0) (P < 0.001).

Conclusions Our results confirm the effectiveness of AZA in inflammatory bowel disease, not only in the short term but also in the long term, resulting in a steroid sparing effect and in both a reduction in the number of hospitalizations and surgical procedures. AZA is similarly effective for both CD and UC patients.
Ninety‐six‐hour wireless oesophageal pH monitoring following proton pump inhibitor administration in NERD patients
Authors: CALABRESE C. , LIGUORI G. , GABUSI V. , GIONCHETTI P. , RIZZELLO F. , STRAFORINI G. , BRUGNERA R. , DI FEBO G.
Published: October 2008

Background  Comparative studies of proton pump inhibitors (PPIs) have revealed that acid reflux is influenced by PPI treatment, formulations and dosing regimens. Wireless pH capsules have circumvented some of the limitations of conventional catheter‐based pH testing with the additional advantage of 96‐h recording periods.

Aim  To clarify the effectiveness of intra‐oesophageal acid suppression by omeprazole, pantoprazole and lansoprazole in non‐erosive reflux disease patients through a 4‐day monitoring of oesophageal pH and related symptoms.

Methods  Twenty‐four patients with typical symptoms of gastro‐oesophageal reflux disease were enrolled and administered upper endoscopy and placement of a wireless pH capsule. Patients randomly received omeprazole, pantoprazole or lansoprazole for 3 days after the first 24 h. Symptom–reflux associations were expressed using the symptom index (SI).

Results  All patients completed the study. Significant decrease in acid exposure occurred on day 2 and in each successive day in all groups. Pantoprazole and omeprazole are more effective than lansoprazole at inducing a normalization of intra‐oesophageal acid exposure at days 2 and 3. Significant reduction in SI at day 2 was observed.

Conclusions  Four‐day ambulatory oesophageal pH monitoring is feasible and safe. Omeprazole, pantoprazole and lansoprazole have an equivalent potency for normalizing intra‐oesophageal acid exposure after 3 days of treatment in non‐erosive reflux disease patients.
The impact of infliximab infusion reactions on long‐term outcomes in patients with Crohn’s disease
Authors: MOSS A. C. , FERNANDEZ‐BECKER N. , JO KIM K. , CURY D. , CHEIFETZ A. S.
Published: October 2008

Background  Little is known about long‐term outcomes in patients who experience infusion reactions while receiving infliximab.

Aim  To investigate long‐term outcomes in patients who experience infusion reactions while receiving infliximab.

Methods  Retrospective electronic chart review of long‐term clinical outcomes.

Results  Clinical data on 287 patients who received infliximab infusions for Crohn’s disease were reviewed, of whom 51 developed at least one infusion reaction (18%). Ileo‐colonic disease (OR 2.2, 95% CI 1.1–4.4) and episodic infliximab (OR 2.4, 95% CI 1.2–4.7) were associated with a higher risk of infusion reactions in univariate analysis, but concomitant azathioprine/mercaptopurine therapy at the initiation of infliximab was associated with a reduced risk (OR 0.4, 95% CI 0.2–0.8). Only the effect of concomitant immunomodulators persisted on multivariate analysis. Patients who experienced infusion reactions were less likely to be in remission at 1 year (OR 0.6, 95% CI 0.3–1.2), 2 years (OR 0.4, 95% CI 0.2–0.8, P = 0.01), or 5 years (OR 0.4, 95% CI 0.1–1.3) and more likely to require surgery (OR 2.2, 95% CI 1.1–4.1, P = 0.01) than those who did not experience such reactions.

Conclusions  Patients who experienced infusion reactions to infliximab had a high rate of discontinuation of therapy in this cohort. Concomitant immunomodulators and maintenance therapy reduced the risk of infusion reactions.
Review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients
Authors: NGUYEN‐KHAC E. , CADRANEL J.‐F. , THEVENOT T. , NOUSBAUM J.‐B.
Published: October 2008

Aliment Pharmacol Ther 28, 282–288

Background  Spontaneous bacterial peritonitis (SBP) can be diagnosed via leucocyte esterase reagent strips, although diagnostic performances vary.

Aim  To perform critical review of literature on the use of reagent strips in SBP.

Methods  Nineteen studies were analysed (Medline search), comparing reagent strips in cirrhotic ascites vs. cytobacteriological methods. Diagnostic grades (G) were: G0 = 0 leucocytes/mm3; G1 = 15; G2 = 70; G3 = 125; G4 = 500 for Multistix, G0 = 0; G1 = 25; G2 = 75; G3 = 500 for Nephur, Combur, UriScan, and G0 = 0; G1 = 25; G2 = 75; G3 = 250; G4 = 500 for Aution.

Results  Medians per study were: 75 patients (range: 31–1041), 136 ascites (47–2123), 17 SBP (5–117). For Multistix (12 studies), the sensitivities fell within the ranges 64.7–100% (G ≥ 1), 45.7–83% (G ≥ 2) and 45.3–89% (G ≥ 3). For Nephur (n = 2), Combur (n = 6), UriScan (n = 1), sensitivities ranged 80.4–100% (G ≥ 1), 63–100% (G ≥ 2) and 67.7–97% (G ≥ 3). For Aution (n = 3), sensitivities ranged 93–96% (G ≥ 2) and 89% (G ≥ 3). Nephur, Combur, UriScan displayed higher sensitivities than Multistix. However, in larger studies, sensitivities dramatically fell at 45.3% for Multistix (G ≥ 3) if ascites polymorphonuclear count <1000/mm3 and 22.2% for bacterascites or 16.7–25% for asymptomatic patients.

Conclusion  Use of reagent strips for the diagnosis of SBP cannot be recommended, in view of low sensitivity and a high risk of false negatives, especially in patients with SBP and low polymorphonuclear count.
Genetic variation in BoLA microsatellite loci in Portuguese cattle breeds
Authors: Bastos‐Silveira C. , Luís C. , Ginja C. , Gama L. T. , Oom M. M.
Published: October 2008

Major histocompatibility complex (MHC) typing based on microsatellites can be a valuable approach to understanding the selective processes occurring at linked or physically close MHC genes and can provide important information on variability and relationships of populations. Using microsatellites within or in close proximity with bovine lymphocyte antigen (BoLA) genes, we investigated the polymorphisms in the bovine MHC, known as the BoLA, in eight Portuguese cattle breeds. Additional data from non‐BoLA microsatellite loci were also used to compare the variability between these regions. Diversity was higher in BoLA than in non‐BoLA microsatellites, as could be observed by the number of alleles, allelic richness and observed heterozygosity. Brava de Lide, a breed selected for aggressiveness and nobility, presented the lowest values of observed heterozygosity and allelic richness in both markers. Results from neutrality tests showed few statistically significant differences between the observed Hardy–Weinberg homozygosity (F) and the expected homozygosity (FE), indicating the apparent neutrality of the BoLA microsatellites within the analysed breeds. Nevertheless, we detected a trend of lower values of observed homozygosity compared with the expected one. We also detected some differences in the levels of allelic variability among the four BoLA microsatellites. Our data showed a higher number of alleles at the BoLA‐DRB3 locus than at the BoLA‐DRBP1 locus. These differences could be related to their physical position in the chromosome and may reflect functional requirements for diversity.
The CADEUS study: burden of nonsteroidal anti‐inflammatory drug (NSAID) utilization for musculoskeletal disorders in blue collar workers
Authors: Rossignol Michel , Abouelfath Abdelilah , Lassalle Regis , Merlière Yvon , Droz Cécile , Bégaud Bernard , Depont Fanny , Moride Yola , Blin Patrick , Moore Nicholas , Fourrier‐Réglat Annie
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• To our knowledge, no study has ever described the intensity of nonsteroidal anti‐inflammatory drug (NSAID) utilization in an employed population by occupation.

• As the use of NSAIDs carries a well‐known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations.

• Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk.

WHAT THIS STUDY ADDS

• In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs.

• No clustering of cyclooxygenase‐2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers.

• The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors.

AIM

The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population.

METHODS

This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’.

RESULTS

Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5‐year history of dyspepsia. No difference was observed between sexes or in the use of COX‐2 selective inhibitors between occupations.

CONCLUSION

Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.
Polymorphisms of drug‐metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa
Authors: Ekhart Corine , Doodeman Valerie D. , Rodenhuis Sjoerd , Smits Paul H. M. , Beijnen Jos H. , Huitema Alwin D. R.
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Thiotepa is metabolized by oxidative desulphuration by the cytochrome P450 (CYP) enzymes CYP2B6 and CYP3A4 to tepa.

• Furthermore, thiotepa and tepa are conjugated to glutathione, which is catalysed by glutathione S‐transferase (GST) isoenzymes A1‐1 and P1‐1.

• Polymorphisms in these enzymes could influence exposure to thiotepa and tepa.

• Little is known about the influence of polymorphisms in these enzymes on the pharmacokinetics of thiotepa and tepa.

WHAT THIS STUDY ADDS

• The presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics.

• We show that probably only the GSTP1 C341T variant allele influences thiotepa exposure to a clinically relevant extent.

AIMS

Thiotepa is widely used in high‐dose chemotherapy. Previous studies have shown relations between exposure and severe organ toxicity. Thiotepa is metabolized by cytochrome P450 and glutathione S‐transferase enzymes. Polymorphisms of these enzymes may affect elimination of thiotepa and tepa, its main metabolite. The purpose of this study was to evaluate effects of known allelic variants in CYP2B6, CYP3A4, CYP3A5, GSTA1 and GSTP1 genes on pharmacokinetics of thiotepa and tepa.

METHODS

White patients (n = 124) received a high‐dose regimen consisting of cyclophosphamide, thiotepa and carboplatin as intravenous infusions. Genomic DNA was analysed using polymerase chain reaction and sequencing. Plasma concentrations of thiotepa and tepa were determined using validated GC and LC‐MS/MS methods. Relations between allelic variants and elimination pharmacokinetic parameters were evaluated using nonlinear mixed effects modelling (nonmem).

RESULTS

The polymorphisms CYP2B6 C1459T, CYP3A4*1B, CYP3A5*3, GSTA1 (C‐69T, G‐52A) and GSTP1 C341T had a significant effect on clearance of thiotepa or tepa. Although significant, most effects were generally not large. Clearance of thiotepa and tepa was predominantly affected by GSTP1 C341T polymorphism, which had a frequency of 9.3%. This polymorphism increased non‐inducible thiotepa clearance by 52% [95% confidence interval (CI) 41, 64, P < 0.001] and decreased tepa clearance by 32% (95% CI 29, 35, P < 0.001) in heterozygous patients, which resulted in an increase in combined exposure to thiotepa and tepa of 45% in homozygous patients.

CONCLUSIONS

This study indicates that the presently evaluated variant alleles explain only a small part of the substantial interindividual variability in thiotepa and tepa pharmacokinetics. Patients homozygous for the GSTP1 C341T allele may have enhanced exposure to thiotepa and tepa.
Variability in the quality of overdose advice in Summary of Product Characteristics (SPC) documents: gut decontamination recommendations for CNS drugs
Authors: Wall Andrew J. B. , Bateman D. N. , Waring W. S.
Published: October 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The Summary of Product Characteristics (SPC) is a legal document that gives healthcare providers information concerning each specific drug, including advice on the management of overdose.

• Clinical outcomes after drug overdose may be influenced by the appropriate use of gut decontamination procedures.

• The extent to which poisoning management advice in the SPC agrees with Poisons Centres recommendations is uncertain.

WHAT THIS STUDY ADDS

• Significant discrepancies exist between poisoning management advice contained in SPC documents and TOXBASE recommendations.

• SPC documents may include inappropriate recommendations for induced emesis and gastric lavage, or omission of oral activated charcoal as a potentially effective therapy.

• The SPC document cannot be relied on as a primary reference source for advice concerning drug overdose.

AIMS

Deliberate self‐poisoning is a major cause of morbidity and mortality. The Summary of Product Characteristics (SPC) document is a legal requirement for all drugs, and Section 4.9 addresses the features of toxicity and clinical advice on management of overdose. The quality and appropriateness of this advice have received comparatively little attention.

METHODS

Section 4.9 of the SPC was examined for all drugs in the central nervous system (CNS) category of the British National Formulary. Advice concerning gut decontamination was examined with respect to specific interventions: induced vomiting, oral activated charcoal, gastric lavage, and other interventions. Data were compared with standard reference sources for clinical management advice in poisoning. These were graded ‘A’ if no important differences existed, ‘B’ if differences were noted but not thought clinically important, and ‘C’ if differences were thought to be clinically significant.

RESULTS

SPC documents were examined for 258 medications from 67 manufacturers. The overall agreement was ‘A’ in 23 (8.9%), ‘B’ in 28 (10.9%) and ‘C’ in 207 (80.2%). Discrepancies were due to inappropriate recommendation of induced emesis in 21.7% (95% confidence interval 17.1, 27.1), gastric lavage in 38.4% (32.7, 44.4), other gut decontamination in 5.8% (3.6, 9.4) and failure to recommend oral activated charcoal in 57.4% (51.1, 63.4).

CONCLUSIONS

Gut decontamination advice in SPC documents with respect to CNS drugs was inadequate. Possible reasons for the observed discrepancies and ways of improving the consistency of advice are proposed.
Use of rituximab in diffuse large B‐cell lymphoma in the salvage setting
Authors: Gisselbrecht Christian
Published: October 2008

The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was a milestone in the development of front‐line therapy for diffuse large B‐cell lymphoma (DLBCL). R‐CHOP and equivalent rituximab‐containing anthracycline‐based regimens are now widely accepted as the standard of care in this setting. However, the optimal treatment for patients with DLBCL relapsing or progressing after front‐line therapy is not yet established. This review explores the role of rituximab in the treatment of DLBCL in the salvage setting, as monotherapy, in combination with chemotherapy or novel agents, and in the context of autologous stem cell transplantation (ASCT). Current evidence suggests that rituximab may improve outcomes in several ways: the higher response rates achieved with rituximab‐based induction in the salvage setting optimize the number of patients who are able to proceed to high‐dose therapy ‐ASCT; rituximab may improve outcomes following ASCT when used as post‐transplantation consolidation/maintenance therapy; and addition of rituximab to salvage regimens may improve outcomes for patients ineligible for transplantation. However, patients refractory to or relapsing after first‐line therapy (including rituximab‐based regimens) still have a poor prognosis. In conclusion, rituximab in salvage therapy for DLBCL is effective and well tolerated. Ongoing studies will further clarify the optimal use of rituximab in the salvage setting.
In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis
Authors: Hausmann M , Obermeier F , Paper D H , Balan K , Dunger N , Menzel K , Falk W , Schoelmerich J , Herfarth H , Rogler G
Published: October 2008

Recently we demonstrated that in inflammatory bowel disease (IBD) macrophage-oxidative burst activity is increased and NADPH oxidase mRNA is induced. The herbal phenylethanoid acteoside isolated from Plantago lanceolata L. was shown to exhibit anti-oxidative potential. Using the dextran sulphate sodium (DSS)-induced colitis model, in this study we have assessed whether systemic application of acteoside affects colitis. Colitis was induced by DSS in Balb/c mice. Treatment with acteoside (120, 600 µg/mouse/day) was performed intraperitoneally. The colon lengths were determined. Colonic tissue was scored histologically (max. score 8) by a blinded investigator. T cells isolated from mesenteric lymph nodes (MLN) were stimulated with anti-CD3 antibody in the presence of interleukin (IL)-2 (final concentration 10 U/ml). After incubation for 24 h, IL-1β, IL-6, IL-12 tumour necrosis factor (TNF)-α and interferon (IFN)-γ levels in supernatants were analysed by the beadlyte® cytokine detection system. Histological scoring of colonic tissue revealed that application of acteoside was followed by a significantly improved histological score. In acute colitis the histological score was 3·2 with acteoside versus 5·2 with phosphate-buffered saline (PBS) (P < 0·02). In chronic colitis both 120 µg (3·3 versus 5·2) or 600 µg acteoside (3·0 versus 5·2) significantly ameliorated colitis (both P < 0·02). Stimulated MLN from mice with chronic DSS-induced colitis treated with acteoside showed a significant down-regulation of IFN-γ secretion (195 pg/ml with 600 µg acteoside versus 612 pg/ml with PBS, P < 0·02). Inhibition of oxidative burst activity with acteoside reduced mucosal tissue damage in DSS colitis and could be a therapeutic alternative for IBD treatment. Further studies of this agent are warranted.