István Rácz

Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study.

Background: The safety and efficacy of fontolizumab, a humanized anti‐interferon gamma antibody, was investigated in patients with Crohns disease (CD). Elevated gut mucosal levels of interferon gamma, a key cytokine involved in the inflammatory process of CD, are associated with disease symptoms. Methods: A total of 201 patients with Crohns Disease Activity Index (CDAI) scores between 250 and 450 were randomized to receive an initial intravenous dose of 1.0 or 4.0 mg/kg fontolizumab or placebo, followed by up to 3 subcutaneous doses of 0.1 or 1.0 mg/kg fontolizumab or placebo every 4 weeks. Clinical response at day 29, the primary efficacy endpoint, was defined as a decrease in the CDAI of at least 100 points from baseline levels. Results: Of 201 patients, 135 (67%) completed the study. Day 29 response rates were similar in all treatment groups (31%–38%). At subsequent timepoints a significantly greater proportion of patients in the 1.0 mg/kg intravenous / 1.0 mg/kg subcutaneous fontolizumab group had clinical response and significantly greater improvement in the CDAI score compared with patients who received placebo. All fontolizumab groups had significant improvement in C‐reactive protein levels. The overall frequency of adverse events was similar in all groups (58%–75%); most events were related to exacerbation of CD. There was a low frequency (5.2%) of neutralizing antibodies to fontolizumab. Conclusions: Although a strong clinical response to fontolizumab was not observed, significant decreases in C‐reactive protein levels suggest a biological effect. Fontolizumab was well tolerated, and further studies to assess its efficacy are warranted. Inflamm Bowel Dis 2009

Characterizing the importance of habitat patches and corridors in maintaining the landscape connectivity of a Pholidoptera transsylvanica (Orthoptera) metapopulation

Since the fragmentation of natural habitats is one of the most serious problems for many endangered species, it is highly interesting to study the properties of fragmented landscapes. As a basic property, landscape connectivity and its effects on various ecological processes are frequently in focus. First, we discuss the relevance of some graph properties in quantifying connectivity. Then, we propose a method how to quantify the relative importance of habitat patches and corridors in maintaining landscape connectivity. Our combined index explicitly considers pure topological properties and topographical measures, like the quality of both patches (local population size) and corridors (permeability). Finally, for illustration, we analyze the landscape graph of the endangered, brachypterous bush-cricket Pholidoptera transsylvanica. The landscape contains 11 patches and 13 corridors and is situated on the Aggtelek Karst, NE-Hungary. We characterize the importance of each node and link of the graph by local and global network indices. We show how different measures of connectivity may suggest different conservation preferences. We conclude, accordingly to our present index, by identifying one specific habitat patch and one specific corridor being in the most critical positions in maintaining connectivity.

A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease.

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease. Trial Registration ClinicalTrials.gov NCT00306215.

Randomised clinical trial: a comparative dose-finding study of three arms of dual release mesalazine for maintaining remission in ulcerative colitis.

Aliment Pharmacol Ther 2011; 33: 313–322

Five-year analysis of the prevention of colorectal sporadic adenomatous polyps trial

OBJECTIVES:Subjects in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial (PRESAP/NCT00141193/www.clinicaltrials.gov) were studied to determine efficacy and safety at a year 5 assessment.METHODS:In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colorectal adenomas removed within 3 months of the studys initiation were assessed after ∼3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratified by cardioprotective aspirin use and randomized to receive orally 400 mg celecoxib (933 subjects) or placebo (628 subjects) once daily. Efficacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment.RESULTS:At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically significantly lower in the celecoxib group (51.4%) than in the placebo group (57.5%; P<0.001). Similarly, the cumulative rate of new advanced adenomas was significantly lower in the celecoxib group (10.0%) than in the placebo group (13.8%; P=0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0%) was 1.66 times more likely to have new adenomas than the placebo group (16.3%; P<0.0001). Similarly, the percentage of patients with new advanced adenomas was significantly higher in the celecoxib group (5.0%) than in the placebo group (3.8%) (P=0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95% confidence interval (CI) 1.01–2.73), selected renal/hypertension events (RR 1.35; 95% CI 1.09–1.68), and general vascular (RR 1.34; 95% CI 1.08–1.68) and cardiac disorders (RR 1.59; 95% CI 1.12–2.26) were higher in those taking celecoxib than in those on placebo.CONCLUSIONS:The year 5 cumulative measures of the incidence of new and advanced adenomas were significantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were significantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxygenase-2 inhibition. Consistent with what has been previously reported, increased risk of renal/hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection.

Population dynamics and genetic changes of Picea abies in the South Carpathians revealed by pollen and ancient DNA analyses

BackgroundStudies on allele length polymorphism designate several glacial refugia for Norway spruce (Picea abies) in the South Carpathian Mountains, but infer only limited expansion from these refugia after the last glaciation. To better understand the genetic dynamics of a South Carpathian spruce lineage, we compared ancient DNA from 10,700 and 11,000-year-old spruce pollen and macrofossils retrieved from Holocene lake sediment in the Retezat Mountains with DNA extracted from extant material from the same site. We used eight primer pairs that amplified short and variable regions of the spruce cpDNA. In addition, from the same lake sediment we obtained a 15,000-years-long pollen accumulation rate (PAR) record for spruce that helped us to infer changes in population size at this site.ResultsWe obtained successful amplifications for Norway spruce from 17 out of 462 pollen grains tested, while the macrofossil material provided 22 DNA sequences. Two fossil sequences were found to be unique to the ancient material. Population genetic statistics showed higher genetic diversity in the ancient individuals compared to the extant ones. Similarly, statistically significant Ks and Kst values showed a considerable level of differentiation between extant and ancient populations at the same loci.Lateglacial and Holocene PAR values suggested that population size of the ancient population was small, in the range of 1/10 or 1/5 of the extant population. PAR analysis also detected two periods of rapid population growths (from ca. 11,100 and 3900 calibrated years before present (cal yr BP)) and three bottlenecks (around 9180, 7200 and 2200 cal yr BP), likely triggered by climatic change and human impact.ConclusionOur results suggest that the paternal lineages observed today in the Retezat Mountains persisted at this site at least since the early Holocene. Combination of the results from the genetic and the PAR analyses furthermore suggests that the higher level of genetic variation found in the ancient populations and the loss of ancient allele types detected in the extant individuals were likely due to the repeated bottlenecks during the Holocene; however our limited sample size did not allow us to exclude sampling effect.This study demonstrates how past population size changes inferred from PAR records can be efficiently used in combination with ancient DNA studies. The joint application of palaeoecological and population genetics analyses proved to be a powerful tool to understand the influence of past population demographic changes on the haplotype diversity and genetic composition of forest tree species.

Association of adherence to therapy and complementary and alternative medicine use with demographic factors and disease phenotype in patients with inflammatory bowel disease.

BACKGROUND AND AIMS Previous studies have suggested an increasing use of complementary and alternative medicine (CAM) in patients with inflammatory bowel disease (IBD). Furthermore, a significant number of IBD patients fail to comply with treatment. The aim of our study was to evaluate the prevalence of non-adherence and the use of CAM in Hungarian patients with IBD. METHODS A total of 655 consecutive IBD patients (CD: 344, age: 38.2 [SD 12.9]years; UC: 311, age: 44.9 [15.3]years) were interviewed during the specialist visit by self-administered questionnaire including demographic and disease-related data as well as items analyzing the extent of non-adherence and CAM use. Patients taking more than 80% of each prescribed medication were classified as adherent. RESULTS The overall rate of self-reported non-adherence (CD: 20.9%, UC: 20.6%) and CAM (CD: 31.7%, UC: 30.9%) use did not differ between Crohns disease (CD) and ulcerative colitis (UC). The most common causes of non-adherence were: forgetfulness (47.8%), too many/unnecessary pills (39.7%), being afraid of side effects (27.9%) and too frequent dosing. Most common forms of CAM were herbal tea (47.3%), homeopathy (14.6%), special diet (12.2%), and acupuncture (5.8%). In CD, disease duration, date of last follow-up visit, educational level and previous surgeries were predicting factors for non-adherence. Alternative medicine use was associated in both diseases with younger age, higher educational level, and immunosuppressant use. In addition, CAM use in UC was more common in females and in patients with supportive psychiatric/psychological therapy. CONCLUSIONS Non-adherence and CAM use is common in patients with IBD. Special attention should be paid to explore the identified predictive factors during follow-up visits to improve adherence to therapy and improving patient-doctor relationship.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - A Hungarian nationwide observational study

BackgroundInfliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohns disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary.MethodsDuring a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy.ResultsThree hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%).ConclusionIFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

Clinical trial: intravenous pantoprazole vs. ranitidine for the prevention of peptic ulcer rebleeding: a multicentre, multinational, randomized trial.

Background  Controlled pantoprazole data in peptic ulcer bleeding are few.

Efficacy and Safety of Adalimumab in Ulcerative Colitis Refractory to Conventional Therapy in Routine Clinical Practice.

BACKGROUND AND AIM Adalimumab [ADA] was approved for the treatment of ulcerative colitis [UC] refractory to conventional therapy in 2012 in Europe. Due to the observed discrepancies between clinical trials and practice, data on the outcome of ADA therapy are really needed from the real life. The aim of this study was to estimate the short- and long-term efficacy and safety of ADA in UC patients from each Hungarian biological centre. PATIENTS AND METHODS This prospective study consisted of UC patients treated with ADA in 10 Hungarian inflammatory bowel disease centres. The primary endpoints of the study were rates of continuous clinical response, remission, non-response and loss of response at Weeks 12, 30, and 52.The secondary endpoints included mucosal healing at Week 52 and the comparison of the efficacy of ADA between biological naive and infliximab [IFX]-treated groups. Colonoscopy was performed before starting the therapy and at Week 52. RESULTS In all, 73 active UC patients were enrolled in the study: 67.1% of the patients received previous IFX therapy; 75.3% of the patients showed short-term clinical response at Week 12. The probability of maintaining ADA was 48.6% at Week 52 with a continuous clinical response in 92% of these remaining patients. Mucosal healing was achieved in 48.1% of the patients at Week 52. Escalation of ADA was performed in 17.6%, and minor side effects developed in 4% of the patients; 5.4% of the patients underwent colectomy during the 1-year treatment period. CONCLUSION UC is a progressive disease that may need early aggressive therapy to prevent structural and functional complications. The results of our study demonstrated the favourable efficacy of short- and long-term ADA treatment for patients with UC.