Amitriptyline modifies the visceral hypersensitivity response to acute stress in the irritable bowel syndrome

Background  Acute physical stress causes alteration in gut autonomic function and visceral hypersensitivity in patients with irritable bowel syndrome (IBS). We have developed a model to measure this stress response.
Aim  To assess whether treatment with a drug effective in treating IBS (amitriptyline) alters the response to acute stress in IBS patients.
Methods  Nineteen patients with IBS were given amitriptyline 25–50 mg. Patients underwent physical stress (cold pressor) test at baseline and after 3 months of treatment. Physiological parameters measured were: stress perception; systemic autonomic tone [heart rate (HR) and blood pressure (BP)]; gut specific autonomic innervation [rectal mucosal blood flow (RMBF)] and visceral sensitivity (rectal electrosensitivity).
Results  Fourteen of 19 (74%) patients improved symptomatically after 3 months of amitriptyline. Acute stress induced increased perception of stress and systemic autonomic tone and reduced RMBF in symptomatic responders and nonresponders ( P  > 0.05 for all). All nonresponders but only 3 of 14 responders continued to exhibit stress-induced reduced pain threshold at 3 months (change from baseline −31% vs. +2%, P  < 0.03 respectively).
Conclusion  In this open study, amitriptyline appears to decrease stress-induced electrical hypersensitivity; this effect is independent of autonomic tone. The gut response to acute stress deserves further study as a model to study drug efficacy in IBS.     

Clinical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study

Background  There is currently no treatment available to manage acute pain attacks in IBS patients regardless of subtype.
Aims  To evaluate efficacy and safety of the GLP-1 analogue ROSE-010 in patients with irritable bowel syndrome (IBS) through a randomized, double-blind, placebo-controlled study.
Methods  Eligible patients ( n  = 166) meeting Rome II criteria were randomly assigned to receive single subcutaneous injections of ROSE-010 100 μg, 300 μg and placebo in a cross-over design. Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Patient-rated pain relief and intensity were measured on a 100-mm visual analogue scale. The primary efficacy variable was proportion of patients with >50% maximum total pain relief response from 10 to 60 min after treatment. Secondary endpoints included the maximum summed pain intensity difference, time to meaningful pain relief and patient ratings of satisfaction with treatment.
Results  Twice as many patients were responders in the primary efficacy endpoint after both ROSE-010 injections compared to placebo (24% P  = 0.011, 23% P  = 0.005, and 12% after 300 μg, 100 μg and placebo injections, respectively). Similar results were obtained for the proportion of patients with total pain intensity response. Times to meaningful and total pain relief were shorter for both doses of ROSE-010 compared with placebo. Compared with placebo, more patients ( P  < 0.05) were satisfied with ROSE-010 and considered ROSE-010 better than previous IBS medications used.
Conclusion  ROSE-010 was well tolerated and provided fast and effective relief of acute pain attacks on demand in IBS patients.     

Clinical trial: the effect of Johrei on symptoms of patients with functional chest pain

Background  Patients with functional chest pain (FCP) represent a therapeutic challenge for practising physicians.
Aim  To determine the efficacy of Johrei as compared to wait-list in improving symptoms of FCP patients.
Methods  Patients with chest pain of noncardiac origin for at least 3 months were enrolled into the study. All patients had to have negative upper endoscopy, pH testing and oesophageal manometry prior to randomization. Subsequently, patients were randomized to either Johrei or wait-list control. Patients received 18 Johrei sessions from a Johrei practitioner for 6 weeks.
Results  A total of 21 FCP patients enrolled into the Johrei group and 18 into the wait-list group. There was no difference in symptom intensity score between Johrei group and wait-list group at baseline (20.28 vs. 23.06, P  = N.S.). However, there was a significant pre- and post-treatment reduction in symptom intensity in the Johrei group (20.28 vs. 7.0, P  =   0.0023). There was no significant reduction in symptom intensity score between baseline and at the end of the study in the wait-list group (23.06 vs. 20.69, P  = N.S.).
Conclusion  This pilot study shows that Johrei may have a role in improving FCP symptoms; however, future studies are needed to compare Johrei treatment with sham Johrei or supportive care.     

Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation

Background  A sensation of abdominal swelling (bloating) and actual increase in girth (distension) are troublesome features of irritable bowel syndrome (IBS), which is more common in patients with constipation, especially those with delayed transit.
Aim  To establish whether a fermented dairy product containing Bifidobacterium lactis DN-173 010 reduces distension in association with acceleration of gastrointestinal transit and improvement of symptoms in IBS with constipation.
Methods  A single centre, randomized, double-blind, controlled, parallel group study in which patients consumed the test product or control product for 4 weeks. Distension, orocaecal and colonic transit and IBS symptoms were assessed on an intention-to-treat population of 34 patients.
Results  Compared with control product, the test product resulted in a significant reduction in the percentage change in maximal distension [median difference – 39%, 95% CI (−78, −5); P  = 0.02] and a trend towards reduced mean distension during the day [−1.52 cm (−3.33, 0.39); P  = 0.096]. An acceleration of orocaecal [−1.2 h (−2.3,0); P  = 0.049] as well as colonic [−12.2 h (−22.8, −1.6); P  = 0.026] transit was observed and overall symptom severity [−0.5 (−1.0, −0.05); P  = 0.032] also improved.
Conclusions  This probiotic resulted in improvements in objectively measured abdominal girth and gastrointestinal transit, as well as reduced symptomatology. These data support the concept that accelerating transit is a useful strategy for treating distension.     

Clinical trial: a randomized controlled cross-over study of flupenthixol + melitracen in functional dyspepsia

Background  Functional dyspepsia is a prevalent condition associated with diminished quality of life (QoL) and high economic burden.
Aim  To study the efficacy of a combination of flupenthixol and melitracen (F + M) with anxiolytic and antidepressant properties in functional dyspepsia using a randomized controlled cross-over design.
Methods  Patients met the Rome III criteria for functional dyspepsia and a validated questionnaire was used to exclude those with anxiety or depression. Moreover, patients had to have failed a trial of acid-suppressive therapy and Helicobacter pylori eradication when positive. End points included subjective global symptom relief and QoL assessed by the Nepean Dyspepsia Index (NDI).
Results  Twenty-five patients (14 females, 11 males; mean age = 34.3 ± 9.9 years) were enrolled and 24 completed the 8-week study. There was a significant improvement in subjective global symptom relief with F + M vs. placebo (ITT: 73.9% vs. 26.1%, P  = 0.001) and a significant drop in the NDI score vs. placebo (ITT: −9.0 ± 11.9 vs. −2.4 ± 8.9, P  = 0.03). No difference was noted whether the initial treatment was F + M or placebo. No significant side effects were noted.
Conclusions  A combination of F and M is safe and effective in the short-term treatment of functional dyspepsia. F + M is associated with significant improvement in QoL independent of the presence of anxiety or depression.     

Efficacy of an intravenous proton pump inhibitor after endoscopic therapy with epinephrine injection for peptic ulcer bleeding in patients with uraemia: a case-control study

Background  Patients with peptic ulcer bleeding and uraemia are prone to re-bleeding.
Aim  To compare the efficacy of an intravenous proton pump inhibitor in treating peptic ulcer bleeding in patients with uraemia and those without uraemia.
Methods  High-risk peptic ulcer bleeding patients received endoscopic therapy with epinephrine (adrenaline) injection plus intravenous omeprazole (40 mg bolus followed by 40 mg infusion every 12 h) for 3 days. Re-bleeding, volume of blood transfusion, hospital stay, need for surgery, and mortality were analysed.
Results  The uraemic group had similar 7-day re-bleeding rate (6/42, 14.29% vs. 6/46, 13.04%, P  =   0.865) to that of non-uraemic patients, but more re-bleeding episodes beyond 7 days (4/42, 9.52% vs. 0/46, 0%, P  =   0.032, OR [95% CI] = 1.105 [1.002–1.219]) and all-cause mortality (4/42 vs. 0/46 P  =   0.032, OR [95% CI] = 1.105 [1.002–1.219]). The uraemic group also had more units of blood transfusion after endoscopic therapy (mean ± s.d. 4.33 ± 3.35 units vs. 2.15 ± 1.65 units, P  <   0.001), longer hospital stay (mean ± s.d. 8.55 ± 8.12 days vs. 4.11 ± 1.60 days, P  <   0.001) and complications during hospitalization (9/42 vs. 0/46, P  =   0.001, OR [95% CI] = 1.273 [1.087–1.490]).
Conclusion  Endoscopic therapy with epinephrine injection plus an intravenous proton pump inhibitor can offer protection against early re-bleeding in uraemic patients with peptic ulcer bleeding, but has a limited role beyond 7 days.     

Clinical trial: effects of botulinum toxin on levator ani syndrome – a double-blind, placebo-controlled study

Background  Levator ani syndrome is characterized by anorectal discomfort/pain, treatment of which is unsatisfactory. We hypothesized that Botulinum toxin relieves spasm and improves symptoms.
Aim  To perform a randomized, placebo-controlled, crossover study to examine the efficacy and safety of botulinum toxin in patients with levator ani syndrome.
Methods  Twelve patients with levator ani syndrome (≥1 year) received anal intra sphincteric injections of 100 units of botulinum toxin A and placebo at 90-day intervals using EMG guidance. Daily frequency, severity, duration and intensity of pain (VAS) were recorded. Anorectal manometry, balloon expulsion and pudendal nerve latency tests were performed to examine the physiological changes and adverse effects.
Results  Seven patients (male/female = 4/3) completed the study and three had incomplete data, but all 10 underwent in an ITT analysis; two others dropped out. After administration of botulinum toxin, the mean frequency, intensity and duration of pain were unchanged ( P  = 0.31) compared with baseline. The 90-day mean VAS pain score was 6.79 ± 0.27 vs. baseline score of 7.08 ± 0.29 ( P  = 0.25). Anal sphincter pressures, rectal sensory thresholds, pudendal nerve latency and balloon expulsion times were unchanged after drug or placebo administration.
Conclusions  Injection of botulinum toxin into anal sphincter is safe, but it does not improve anorectal pain in levator ani syndrome.     

Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study

Background  Intestinal immune infiltration contributes to symptoms in patients with irritable bowel syndrome (IBS).
Aim  To assesses the effect of mesalazine (mesalamine) on mucosal immune cells in patients with IBS, through a pilot study.
Methods  A randomized, double-blind, placebo-controlled trial in 20 patients with IBS in tertiary care setting. Patients were randomized to receive placebo or 800 mg mesalazine three times daily for 8 weeks. The primary endpoint was a significant reduction in total colonic immune cells on biopsies obtained at the end of treatment compared to baseline. Secondary endpoints included effects on subsets of immune cells, inflammatory mediators and symptom severity. Intention-to-treat analysis was performed.
Results  Mesalazine markedly reduced immune cells as compared with placebo ( P  = 0.0082); this effect was ascribed to a marked inhibition of mast cells ( P  = 0.0014). Mesalazine significantly increased general well-being ( P  = 0.038), but had no significant effects on abdominal pain ( P  = 0.084), bloating ( P  = 0.177) or bowel habits. No serious drug-related adverse events were reported during the study.
Conclusions  Mesalazine is an effective and safe approach to reduce mast cell infiltration and may improve general well-being in patients with IBS. These results support the hypothesis that immune mechanisms represent potential therapeutic targets in IBS.     

The influence of co-morbid IBS and psychological distress on outcomes and quality of life following PPI therapy in patients with gastro-oesophageal reflux disease

Background  A subset of patients with gastro-oesophageal reflux disease (GERD) does not achieve complete symptom resolution with proton pump inhibitor (PPI) therapy. The factors which affect response to PPI therapy in GERD patients remain unclear.
Aims  To determine the prevalence and impact of irritable bowel syndrome (IBS) and psychological distress (PD) on GERD symptoms and disease-specific quality of life (QoL) before and after PPI therapy and to assess the same outcomes before and after PPI therapy in non-erosive reflux disease (NERD) and erosive oesophagitis (EO) GERD patients.
Methods  Patients undergoing oesophago-gastroduodenoscopy (OGD) for heartburn were recruited. Participants completed validated surveys: Digestive Health Symptom Index, Reflux Disease Questionnaire, Quality of Life in Reflux and Dyspepsia and Brief Symptom Inventory (BSI). IBS was defined as >3 Manning criteria and PD as BSI score >63. At OGD, patients were classified as NERD or EO. Patients were treated with rabeprazole 20 mg/day for 8 weeks before completing follow-up surveys.
Results  Of 132 GERD patients enrolled, 101 completed the study. The prevalence rates of IBS and PD were 36% and 41%, respectively. IBS independently predicted worse QoL before and after PPI therapy. PD independently predicted worse GERD symptoms and QoL before and after PPI therapy. There were no differences in symptoms or QoL between NERD and EO patients before or after PPI therapy.
Conclusions  IBS and PD impacted GERD symptoms and QoL before and after PPI therapy. Symptoms and QoL before and after PPI therapy were similar in NERD and EO patients.     

Irritable bowel syndrome and dyspepsia among women veterans: prevalence and association with psychological distress

Background  The burden of functional GI disorders and their associations with psychological distress in women veterans is unclear.
Aim  To examine 1-year prevalence of irritable bowel syndrome (IBS) and dyspepsia symptoms and their associations with anxiety, depression and post-traumatic stress disorder (PTSD) among women veterans receiving primary care at a Veteran Affairs Medical Center Women's Clinic.
Methods  Irritable bowel syndrome, dyspepsia and psychological distress were assessed using the validated self-administered Bowel Disorder Questionnaire, the Beck Depression and Anxiety Inventories, as well as the Mississippi Scale for Combat-Related Post-Traumatic Stress Disorder Questionnaire.
Results  We enrolled 248 women (84% participation rate). Ninety-three (38%) reported IBS and 51 (21%) dyspepsia symptoms. Women with IBS and dyspepsia reported higher mean scores of anxiety (IBS: 24 vs. 12, P  < 0.0005 and dyspepsia: 26 vs. 12, P  < 0.0005), depression (IBS: 22 vs. 11, P  = 0.0005 and dyspepsia: 23 vs. 11, P  < 0.0005) and PTSD (IBS: 87 vs. 69, P  < 0.001 and dyspepsia: 86 vs. 69, P  < 0.0005). Age- and ethnicity-adjusted logistic regression analyses showed a 3- to 46-fold increase in odds of IBS and dyspepsia among women with anxiety, depression or PTSD.
Conclusion  Women veterans have high prevalence of IBS and dyspepsia symptoms, both of which are highly associated with presence of depression, anxiety and PTSD.     

Post-inflammatory modification of colonic afferent mechanosensitivity

1. The present review discusses interactions between the immune and nervous systems in post-infectious irritable bowel syndrome (PI-IBS).
2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology.
3. The PI-IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as Campylobacter or Salmonella . Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli.
4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1-mediated inflammatory response, consistent with clinical observations in PI-IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage.
5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI-IBS.     

The citrulline generation test: proposal for a new enterocyte function test

Background  The amino acid citrulline is mainly produced by enterocytes from conversion of glutamine. As fasting plasma citrulline proved disappointing as a biomarker for enterocyte dysfunction in clinical practice, we propose a citrulline generation test (CGT) to assess enterocyte function.
Aim  To assess the feasibility of a CGT in healthy subjects and patients with decreased enterocyte mass.
Methods  Nineteen healthy subjects, 16 patients with intestinal villous atrophy and nine patients with short bowel syndrome (SBS) were given an oral bolus of 20 g of the dipeptide alanine–glutamine. Subsequent changes in plasma citrulline and other amino acid concentrations were determined using reverse-phase high-performance liquid chromatography.
Results  Following the oral bolus of alanine–glutamine, plasma citrulline concentrations showed a time dependent rise in healthy subjects of 44 ± 13% (38–55 μmol/L, P  < 0.0001). The slope from baseline plasma citrulline to peak concentrations was 0.22 ± 0.08, 0.13 ± 0.04 and 0.09 ± 0.04 μmol/L/min in healthy subjects, patients with coeliac disease (CeD) and refractory CeD, respectively (healthy subjects vs. CeD P  < 0.05, healthy subjects vs. refractory CeD P  < 0.001). In patients with SBS, the CGT was able to distinguish between non-adapted and adapted SBS by means of the incremental area under the CGT curve till 90 min (iAUC T90). The iAUC T90 was 447 ± 179 and 1039 ± 178 μmol/L/min in non-adapted and adapted SBS, respectively ( P  = 0.04).
Conclusion  An oral bolus of alanine–glutamine induces a time-dependent rise in plasma citrulline concentration to an extent dependent on the existence of villous atrophy or enterocyte hyperplasia in CeD, and adapted SBS, respectively.     

The effect of a single rectal dose of cisapride on delayed gastric emptying

Background : Cisapride has an established prokinetic effect in patients with delayed gastric emptying. However, rectal administration of the drug might be preferred in patients with either dysphagia or nausea due to gastroparesis.
Aim : To determine the effect of a single rectal dose of cisapride 60 mg on gastric emptying in patients with delayed gastric emptying.
Methods : Thirty-two patients (16 males, 16 females) with demonstrated delayed gastric emptying received a single dose of two suppositories containing either cisapride (2 × 30 mg) or placebo, according to a double-blind randomized crossover design. Three hours after administration of the suppositories, the patients received a radio-labelled test meal and radio-opaque markers for measurement of gastric emptying.
Results : The mean t _½ after cisapride administration (76 min, 95% CI: 68–95) was significantly shorter ( P  = 0.005; n  = 28, per-protocol analysis) than after placebo administration (104 min, 81–126). Four hours after ingestion of the meal significantly fewer radio-opaque markers remained in the stomach after cisapride than after placebo administration ( P  < 0.05). Mild to moderate adverse events, mainly involving the gastrointestinal tract, were reported in 10 patients (31%) after cisapride treatment and in four patients (13%) after placebo (N.S.; n  = 32).
Conclusion : A single suppository dose of cisapride 60 mg significantly accelerates gastric emptying of the solid phase of a meal and of radio-opaque markers in patients with previously demonstrated delayed gastric emptying.     

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study

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.     

Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome

Background  Dextofisopam modulates stimulated activity in animal models of stress, altered bowel motility, and visceral hypersensitivity.
Aim  To evaluate the effects of dextofisopam in men and women with diarrhoea-predominant or alternating irritable bowel syndrome (IBS) (d-IBS or a-IBS).
Methods  In this double-blind, placebo-controlled study, patients were randomly assigned to receive dextofisopam 200 mg b.d. or placebo for 12 weeks. The prospectively defined primary endpoint was number of months of adequate overall relief of IBS symptoms. Bowel function was assessed primarily via stool frequency and consistency.
Results  Of 140 enrolled patients, 66 received dextofisopam and 74 placebo; 73% of the patients were women, and 78% had d-IBS. Dextofisopam was superior to placebo on the primary endpoint ( P  = 0.033). In d-IBS patients treated with dextofisopam, both men and women had improved stool consistency, but stool frequency was reduced only in women. Benefit diminished over time on the primary endpoint, but persisted on frequency and consistency. Dextofisopam and placebo had similar rates and types of adverse events, with more events of worsening abdominal pain with dextofisopam (12% vs. 4%) and more headaches with placebo (12% vs. 5%). Constipation was rare.
Conclusion  Dextofisopam should be further evaluated as a new treatment for men and women with d-IBS and a-IBS.     

Asimadoline, a kappa-opioid agonist, and satiation in functional dyspepsia

Background  Asimadoline, a kappa-opioid agonist, reduces visceral sensitivity in experimental animal models and may decrease satiation and postprandial fullness in healthy individuals. However, its effect on satiation in functional dyspepsia is unclear, and any symptom benefit has not been explored.
Aim  To evaluate the effects of asimadoline on satiation volume and postchallenge symptoms in functional dyspepsia.
Methods  A randomized, double-blind trial evaluated gastric satiation and symptoms before and after 8 weeks of asimadoline 0.5 mg ( n  = 13) or 1.0 mg ( n  = 13) or placebo ( n  = 14) b.d. in patients with functional dyspepsia (Rome II). Gastrointestinal Symptom Rating Scale and Nepean Dyspepsia Index were used to assess symptoms during the 8-week treatment.
Results  Over 8 weeks of treatment, asimadoline had no significant effect on maximum-tolerated volume or aggregate symptom score with nutrient drink challenge, and on the mean of the total daily symptom severity score compared to placebo. In a post hoc analysis, asimadoline 0.5 mg significantly increased the maximum-tolerated volume (1217 mL ± 90.2) compared to placebo (807 mL ± 111.8) in patients with higher postprandial fullness scores ( P  = 0.01).
Conclusion  Asimadoline overall did not significantly alter maximum-tolerated volume, symptoms postnutrient challenge or symptoms over 8 weeks in functional dyspepsia.     

Clinical trial: low plasma cholesterol and oxidative stress predict rapid virological response to standard therapy with peginterferon and ribavirin in HCV patients

Background  Rapid virological response (RVR) is the best predictor of sustained response to standard HCV treatment.
Aim  To evaluate predictive factors of RVR.
Methods  Sixty-five patients (mean age 52.6 ± 13.8; 37 genotype-1, and 28 genotypes-2/3) were consecutively treated with pegIFN-alpha2a or 2b once weekly plus daily ribavirin based on body weight for 24 or 48 weeks, according to genotype. RVR was defined as undetectable HCV-RNA at week 4.
Results  Twenty-seven percent of patients achieved RVR in genotypes 1 and 60.7% in genotypes 2/3 ( P  < 0.01). Rapid responders had higher mean serum baseline total and LDL-cholesterol levels ( P  < 0.01). RVR was 20.0% in the bottom tertile of total cholesterol and 63.6% in the top tertile ( P  < 0.01). HCV-RNA levels at week 4 were positively correlated with baseline serum insulin ( P  < 0.01), HOMA-IR ( P  < 0.01), body mass index ( P  < 0.05) and number of components of metabolic syndrome ( P  < 0.01) and negatively correlated with cholesterol levels ( P  < 0.05). At multivariate analysis, age, LDL-cholesterol, HCV genotype and serum 8-iso-PGF2alpha, a marker of oxidative stress, were independent predictors of RVR.
Conclusions  Our prospective study supports a role of low serum total and LDL-cholesterol and of oxidative stress as positive independent predictive factors of poor RVR in HCV patients.     

Serum gastrin and pepsinogens do not correlate with the different grades of severity of gastro-oesophageal reflux disease: a matched case-control study

Background  Gastrin and pepsinogens reflect the functional state of the gastric mucosa.
Aim  To evaluate whether serum gastrin and pepsinogens correlate with the different grades of severity of gastro-oesophageal reflux disease (GERD).
Methods  In all, 388 patients with heartburn not taking any form of acid suppressive therapy were matched-controlled for age and gender and sub-classified into four groups: group 1 non-erosive reflux disease (NERD); group 2, erosive reflux disease (ERD) Los Angeles (LA) A and B, group 3, ERD LA C and D; group 4 Barrett's oesophagus (BO). Fasting serum was analysed for gastrin 17, pepsinogen I, pepsinogen II und Helicobacter pylori using specific EIA tests (GastroPanel; Biohit, Plc). Statistics: Kruskal–Wallis test and analysis of variance.
Results  There was a significant difference among the four groups with respect for pepsinogen I, but not for pepsinogen II, the pepsinogen I pepsinogen II ratio, H. pylori serology and gastrin levels. Pepsinogen I was the lowest in NERD and the highest in BO (median 91.6, mean ± standard deviation 106.2 ± 51.6 vs. median 114.7, mean ± standard deviation 130.4 ± 70.6; P  = 0.046). Pepsinogen I levels were higher in H. pylori positive subjects. After adjusting for H. pylori status, the differences in pepsinogen I across patient groups were no longer statistically significant ( P  = 0.298).
Conclusions  Serum gastrin and pepsinogen I and II do not correlate with the different grades of severity of GERD. The non-invasive GastroPanel is not useful for the differentiation of the various forms of GERD.     

Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease

Background : The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis.
Aim : The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease.
Subjects and methods : NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy-proven cirrhosis (Child's grade; 1 A, 4 B, 4 C; aetiology: 7 alcohol-related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg.
Results : The area under the serum concentration–time curve was increased (152.34 mg/L.h ± 50.38 s.d.) in cirrhotics compared with normal controls; (93.86 mg/L.h ± 9.60 s.d.) ( P  < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h ± 1.87 s.d.) compared with controls (6.47 L/h ± 0.78; P  < 0.01).
Conclusions : Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.     

Systematic review: nutritional support in acute pancreatitis

Background  There has been controversy concerning the merits of enteral and parenteral nutrition compared with no supplementary nutrition in the management of patients with acute pancreatitis.
Aim  To perform a systematic review of the data from randomized controlled trials (RCTs) in acute pancreatitis that compares enteral nutrition with no supplementary nutrition, parenteral nutrition with no supplementary nutrition and enteral nutrition with parenteral nutrition.
Methods  A search was undertaken in the MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials.
Results  Fifteen RCTs were included. Enteral nutrition, when compared with no supplementary nutrition, was associated with no significant change in infectious complications: ratio of relative risks (RR) 0.56, 95% confidence interval (CI) 0.07–4.32, P  = 0.58, but a significant reduction in mortality: ratio of RR 0.22, 95% CI 0.07–0.70, P  = 0.01. Parenteral nutrition, when compared with no supplementary nutrition, was associated with no significant change in infectious complications: RR 1.36, 95% CI 0.18–10.40; P  = 0.77, but a significant reduction in mortality: RR 0.36, 95% CI 0.13–0.97, P  = 0.04. Enteral nutrition, when compared with parenteral nutrition, was associated with a significant reduction in infectious complications: RR 0.41, 95% CI 0.30–0.57, P  < 0.001, but no significant change in mortality: RR 0.60, 95% CI 0.32–1.14, P  = 0.12.
Conclusions  The use of either enteral or parenteral nutrition, in comparison with no supplementary nutrition, is associated with a lower risk of death in acute pancreatitis. Enteral nutrition is associated with a lower risk of infectious complications compared with parenteral nutrition.