Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

BACKGROUND: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN: Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING: 10 university and 11 academic hospitals in Germany. PATIENTS: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION: Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS: The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS: 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS: Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE: Roche Pharma and Lundbeck.

Influence of gender on cytokine induced depression and treatment: Gender aspects of IFN-α-induced depression.

BACKGROUND: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. METHODS: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. RESULTS: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. CONCLUSIONS: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Validation of the X-Vision ERCP Training System and technical challenges during early training of sphincterotomy.

BACKGROUND & AIMS: A new fluoroscopy-free training system for endoscopic retrograde cholangiopancreatography (ERCP) with different model subtypes recently was developed. This study aimed to establish construct validity by investigating whether the X-Vision ERCP Training System could distinguish experienced endoscopists from beginners and to reveal characteristic mistakes during sphincterotomy. METHODS: Six staff gastroenterologists that practice ERCP, 10 trainees that perform esophagogastroduodenoscopy and colonoscopy, and 12 residents without endoscopic experience each sequentially attempted 4 different models, simulating selective cannulation of the pancreatic or bile duct, intubation of differently arranged rubber papillas, stent placement, and sphincterotomy of a biopapilla. Performance parameters were recorded and participants' expectations were compared before and after training to determine whether the simulator was a credible tool for ERCP training. Staff gastroenterologists graded the realism and utility of the simulation. The quality of sphincterotomy was assessed by an expert endoscopist. RESULTS: Participants with ERCP experience had significantly shorter procedure times compared with those with intermediate (P < .001) or no endoscopic experience (P < .001). Total and single credibility scores significantly increased after simulator practice. The faculty found the X-Vision ERCP Training System to be realistic and useful for training. In the less-experienced groups, common mistakes made during sphincterotomy included inadequate positioning of the duodenoscope, traumatic intubation of the papilla, and continued cutting despite insufficient endoscopic view. CONCLUSIONS: The X-Vision ERCP Training System distinguished subjects with different levels of experience and was regarded as realistic and useful for ERCP training. Common mistakes during sphincterotomy could be assessed objectively.

Placebo-controlled trial of 400 mg amantadine combined with peginterferon alfa-2a and ribavirin for 48 weeks in chronic hepatitis C virus-1 infection.

UNLABELLED: The impact of amantadine on virologic response rates of interferon-based treatment of chronic hepatitis C is controversial. The aim of this study was to compare virological response rates in patients with chronic hepatitis C virus (HCV)-1 infection treated with 400 mg amantadine or placebo in combination with peginterferon alfa-2a (40 kD) and ribavirin for 48 weeks. Seven hundred four previously untreated chronically HCV-1-infected patients (mean age, 46 +/- 12 years) were randomized to (A) amantadine-sulphate (400 mg/day) (n = 352) or (B) placebo (n = 352), both in combination with 180 microg peginterferon alfa-2a once weekly and ribavirin (1000-1200 mg/day) for 48 weeks. End of treatment and sustained virological response after a 24-week follow-up period were assessed by qualitative reverse transcription polymerase chain reaction (RT-PCR) (sensitivity, 50 IU/mL). Demographic and baseline virological parameters were similar in both treatment groups. In groups A and B, 231 of 352 patients (66%) and 256 of 352 patients (72%) achieved an end of treatment response, and 171 of 352 patients (49 %) and 186 of 352 patients (53 %) a sustained virological response, respectively. On-treatment dropout rate in the amantadine group was significantly higher than in the placebo group (32% versus 23%; P = 0.01). However, adverse events and laboratory abnormalities were similar between both groups. Per-protocol analysis revealed similar sustained virological response rates in both treatment groups (53% versus 55%). CONCLUSION: In this large placebo-controlled multicenter study, amantadine even at a dose of 400 mg/day did not improve virological response rates of peginterferon alfa-2a and ribavirin in patients with chronic genotype HCV-1 infection.

In vitro activity of moxifloxacin and piperacillin/sulbactam against pathogens of acute cholangitis.

AIM: To analyze the in vitro activity of moxifloxacin and piperacillin/sulbactam against pathogens isolated from patients with acute cholangitis. METHODS: In this prospective study a total of 65 patients with acute cholangitis due to biliary stone obstruction (n = 7), benign biliary stricture (n = 16), and malignant biliary stricture (n = 42) were investigated with regard to spectrum of bacterial infection and antibiotic resistance. Pathogens were isolated from bile cultures in all study patients. In 22 febrile patients, blood cultures were also obtained. In vitro activity of moxifloxacin and piperacillin/sulbactam was determined by agar diffusion. RESULTS: Thirty-one out of 65 patients had positive bile and/or blood cultures. In 31 patients, 63 isolates with 17 different species were identified. The predominant strains were Enterococcus species (26/63), E.coli (13/63) and Klebsiella species (8/63). A comparable in vitro activity of moxifloxacin and piperacillin/sulbactam was observed for E.coli and Klebsiella species. In contrast, Enterococcus species had higher resistances towards moxifloxacin. Overall bacteria showed antibiotic resistances in vitro of 34.9% for piperacillin/sulbactam and 36.5% for moxifloxacin. CONCLUSION: Enterococcus species, E.coli and Klebsiella species were the most common bacteria isolated from bile and/or blood from patients with acute cholangitis. Overall, a mixed infection with several species was observed, and bacteria showed a comparable in vitro activity for piperacillin/sulbactam and moxifloxacin.

Endoscopic transpapillary brush cytology and forceps biopsy in patients with hilar cholangiocarcinoma.

AIM: To evaluate the sensitivity of brush cytology and forceps biopsy in a homogeneous patient group with hilar cholangiocarcinoma. METHODS: Brush cytology and forceps biopsy were routinely performed in patients with suspected malignant biliary strictures. Fifty-eight consecutive patients undergoing endoscopic retrograde cholangio-pancreatography (ERCP) including forceps biopsy and brush cytology in patients with hilar cholangiocarcinoma between 1995-2005. RESULTS: Positive results for malignancy were obtained in 24/58 patients (41.4%) by brush cytology and in 31/58 patients (53.4%) by forceps biopsy. The combination of both techniques brush cytology and forceps biopsy resulted only in a minor increase in diagnostic sensitivity to 60.3% (35/58 patients). In 20/58 patients (34.5%), diagnosis were obtained by both positive cytology and positive histology, in 11/58 (19%) by positive histology (negative cytology) and only 4/58 patients (6.9%) were confirmed by positive cytology (negative histology). CONCLUSION: Brush cytology and forceps biopsy have only limited sensitivity for the diagnosis of malignant hilar tumors. In our eyes, additional diagnostic techniques should be evaluated and should become routine in patients with negative cytological and histological findings.

Treatment of chronic hepatitis B with high-dose intravenous N-acetyl-L-cysteine.

BACKGROUND/AIMS: Therapy of hepatitis B with alpha-interferon is only successful in 30-40%; therefore new therapeutic options are needed. N-acetyl-L-cysteine is well known as an antidote against paracetamol intoxication and as mucolytic agent in pulmonary diseases. Furthermore, it restrains human immunodeficiency virus replication and inhibits hepatitis B virus replication at a posttranscriptional level in vitro. This study aims to evaluate the efficacy of N-acetyl-L-cysteine in 5 patients chronically infected with hepatitis B virus. METHODOLOGY: N-acetyl-L-cysteine was given intravenously at a daily dose of 150 mg/kg body weight. Treatment was performed for 28 days. RESULTS: The N-acetyl-L-cysteine infusions were tolerated without any side effects. Except a mild increase in thrombocyte-counts within the last week of N-acetyl-L-cysteine infusion blood tests did not change. We could not detect any changes in quantitative hepatitis B virus-DNA levels as well as in the HBeAg-status. CONCLUSIONS: We conclude from our data that N-acetyl-L-cysteine given in a high dose intravenously for 28 days is well tolerated. In contrast to in vitro studies no significant effects on the hepatitis B-virus load were detectable in vivo.

Long-term outcome of endoscopic and/or percutaneous transhepatic therapy in patients with biliary stricture after orthotopic liver transplantation.

BACKGROUND: Biliary strictures are a serious complication after liver transplantation. Endoscopic and percutaneous transhepatic procedures have gained an increasing potential for the management of this problem. OBJECTIVE: Long-term follow-up of endoscopic and/or percutaneous transhepatic therapy of biliary strictures after liver transplantation was evaluated. PATIENTS AND METHODS: Between January 1996 and December 2007, 47 patients with biliary stricture after liver transplantation were identified by analysing the endoscopic database, hospital charts and cholangiograms. Long-term follow-up was evaluated using cholangiograms, transabdominal ultrasound, laboratory parameters and physical examination. RESULTS: The type of biliary stricture after liver transplantation was subdivided into anastomotic stricture (n = 29), non-anastomotic stricture (n = 14) and bilioenterostomy stricture (n = 4). Of the patients, 38/47 were treated by endoscopic procedures (ERCP), and 9/47 patients were treated by percutaneous transhepatic procedures (PTBD). In 2 of 47 patients combined approaches (rendezvous technique) were performed. Overall, 23/29 patients in the anastomotic group, 12/14 patients in the non-anastomotic group, and 3/4 patients in the bilioenterostomy group had successfully completed endoscopic and/or percutaneous transhepatic therapy. Biliary drainage could be respectively terminated after median 9 (1-83), 11 (1-89) and 10 (4-14) months. CONCLUSIONS: Endoscopic as well as percutaneous transhepatic approaches in combination or as monotherapy are effective in the management of anastomotic and non-anastomotic strictures after liver transplantation.

Acute experimental pancreatitis and NF-kappaB/Rel activation.

Acute pancreatitis is a serious disease with a high morbidity and an overall mortality rate of about 10%. However, in its most severe form, which is characterized by pancreatic necrosis, 20-30% of the patients die. Death is often the result of multiorgan dysfunction, including acute respiratory, kidney, and hepatic failure as well as generalized diffuse capillary leak water retention, hypoxia, and acid/base disturbance. The mechanisms by which distant organ systems are involved still remain obscure, but several lines of evidence suggest the participation of cytokines (IL-1, IL-6, and TNF-alpha) as a response to local tissue damage. A series of studies have now shed new light on the pivotal pathogenic role of the transcription factor NF-kappaB/Rel that binds to the promoter regions of many proinflammatory genes and regulates their transcription.

Induction of IkappaB-kinase by cholecystokinin is mediated by trypsinogen activation in rat pancreatic lobules.

BACKGROUND AND AIMS: Supramaximal concentrations of cholecystokinin (CCK) or cerulein induce the intracellular activation of trypsinogen and the transcription factor NF-kappaB, a key regulator of inflammatory gene expression. Both events occur early in the development of an acute pancreatitis. The aim of this study was to examine the relationship between intracellular trypsinogen and NF-kappaB activation. METHODS: We detected NF-kappaB-binding activity in electromobility shift assays, IkappaB proteolysis in Western analysis and endogenous IkappaB-kinase (IKKalpha and beta) activation using immune complex kinase assays following treatment with CCK in rat pancreatic lobules. To block intrapancreatic trypsinogen activation, a potent and cell-permeable serine-protease inhibitor, Pefabloc, was used. RESULTS: CCK-induced IkappaBalpha degradation and subsequent NF-kappaB activation correlated closely with the catalytic activity of IKKs to phosphorylate IkappaBalpha in vitro. Activation is dose-dependent and peaked at 30 min. Doses of Pefabloc sufficient to inhibit trypsin activation reduced CCK-induced activation of NF-kappaB whereas TNF-alpha-induced NF-kappaB activation was not blocked but slightly increased. Moreover, treatment with Pefabloc as well as another serine protease inhibitor, FUT175, inhibited CCK-induced IKK activation. CONCLUSION: These results suggest that intrapancreatic activation of trypsinogen may contribute to NF-kappaB signaling via IKK activation in cerulein pancreatitis. This also explains the fact that only doses of CCK which activate trypsinogen induce NF-kappaB activation in pancreatic acinar cells. Thus, trypsinogen activation is likely to modulate signaling events in acinar cells in the initial phase of acute pancreatitis.

Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy.

The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.

IL-10 increases tissue injury after selective intestinal ischemia/reperfusion.

OBJECTIVE This study focused on the effect of immunoregulatory cytokines on tissue injury after intestinal ischemia/reperfusion (IR). Furthermore, the role of nitric oxide, heme oxygenase-1 (HO-1) and the transcription factor NF-kappaB/Rel in the disease process was evaluated.SUMMARY BACKGROUND DATA Oxidative stress and inflammatory gene products contribute to ischemia/reperfusion injury (IRI). However, expression of stress proteins such as the inducible nitric oxide synthase (NOS-2) and HO-1 might also provide protection against IRI. METHODS IR was achieved in Lewis rats by selective clamping of the superior mesenteric artery. IL-2 or IL-10 was administered intravenously before reperfusion. Animals were killed 1 hour, 4 hours, and 24 hours after reperfusion. Tissue destruction was assessed by hyaluronic acid (HA) and aminoaspartate-transaminase (AST) serum levels, whereas reduction of glutathione (GSH) tissue levels was used as a marker for oxidative stress. Furthermore, the activation of NF-kappaB/Rel and the expression of NOS-2 and HO-1 were analyzed.RESULTS IR resulted in tissue destruction and significantly reduced GSH tissue levels in the intestines and liver. In addition, NF-kappaB/Rel activation and increased NOS-2 and HO-1 mRNA expression were detected in both organs after IR. IL-2 administration resulted in clinical improvement of the animals and was associated with increased NF-kappaB/Rel activation and enhanced NOS-2 and HO-1 mRNA expression. In contrast, IL-10 resulted in increased tissue destruction in both organs and sustained reduction of GSH levels in the intestines. Furthermore, IL-10 administration failed to enhance NF-kappaB/Rel activity, NOS-2 mRNA, or HO-1 mRNA expression after IR. CONCLUSION IL-10 resulted in increased tissue damage after intestinal IR. This detrimental effect of IL-10 might have been the result of reduced NOS-2 and HO-1 mRNA expression. In contrast, the beneficial effect of IL-2 might have relied on increased HO-1 expression and NOS-2 activity. These controversial effects of IL-2 and IL-10 might have been mediated through transcriptional regulation of NOS-2 and HO-1 gene expression.