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K R Herrlinger

Publications and source records attributed to K R Herrlinger.

16 recordsLinked to original sources
PubMed2006

Review article: interactions between genotype and response to therapy in inflammatory bowel diseases.

BACKGROUND: More than half of the patients with inflammatory bowel diseases are candidates for immunosuppressive therapy. However, even the most effective drugs used in inflammatory bowel disease are only successful in about two-thirds of patients. Adverse events limit their use in a further substantial proportion of patients. Recent research has focussed on the possibility of predicting a drugs' efficacy and/or toxicity by identifying polymorphic variants in the genes encoding enzymes involved in metabolic pathways. AIM: To highlight recent advances and limitations in the field of pharmacogenetics in inflammatory bowel disease. RESULTS: Recent pharmacogenetic studies have mainly focussed on immunosuppressive agents including corticosteroids, azathioprine, methotrexate and infliximab. Several polymorphic genes encoding enzymes involved in the metabolism of these drugs have been identified including the inosine triphosphate pyrophosphatase in thiopurine therapy, the methylene tetrahydrofolate reductase in methotrexate therapy and polymorphisms in apoptosis genes in infliximab therapy. However, at the present time, genotyping for the variants of the thiopurine methyltransferase gene, an enzyme important for the metabolism of the thiopurine drugs, is the only useful test in clinical practice. CONCLUSIONS: Although the field of pharmacogenetics in inflammatory bowel disease is promising most new targets have so far failed to translate into clinical practice. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner.

Anti-Inflammatory Agents↗
PubMed2006

6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party.

Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity.

Antimetabolites, Antineoplastic↗
PubMed2006

Tacrolimus--finally!

Explore the source record for details and available documents.

Administration, Oral↗
PubMed2005

Oral methotrexate in ulcerative colitis.

BACKGROUND: We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. METHODS: Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). RESULTS: There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). CONCLUSION: Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.

Adolescent↗
PubMed2004

Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease.

BACKGROUND: 6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine. AIM: To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease. METHODS: 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity. RESULTS: 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine-nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels. CONCLUSIONS: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.

Adult↗
PubMed2004

NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.

BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

Adolescent↗
PubMed2003

Remission maintenance by tioguanine in chronic active Crohn's disease.

BACKGROUND: Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission. AIM: To evaluate the role of tioguanine in the maintenance of remission in chronic active Crohn's disease. METHODS: A follow-up study was performed to investigate the long-term efficacy and safety of and tolerance to tioguanine in chronic active Crohn's disease. Sixteen patients who had successfully received 6-tioguanine for remission induction were enrolled. The reasons for immunosuppressive therapy were steroid dependence (n = 10), steroid refractoriness (n = 6) and intolerance (n = 6) or refractoriness (n = 1) to azathioprine. After remission induction therapy for 6 months, patients were treated for another 6 months with a daily dose of 20-40 mg tioguanine. Primary outcomes were remission (Crohn's disease activity index < 150) and complete steroid reduction in steroid-dependent patients at 12 months. Laboratory controls of white blood count and liver enzymes, as well as erythrocyte tioguanine nucleotide levels, were performed regularly. RESULTS: After 12 months of treatment, 14 of 16 (88%) patients were in remission, and 12 of these were completely free of systemic steroids. Adverse events during maintenance therapy included photosensitivity (one patient), minor viral infections (one), headache (four) and mild alopecia (one). One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia, indicative of nodular regenerative hyperplasia of the liver. CONCLUSIONS: In responders to tioguanine, the drug appears to be very effective in maintaining remission of chronic active Crohn's disease. Unfortunately, long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction. Therefore, to date, tioguanine cannot be recommended for general use outside clinical trials.

Adult↗
PubMed2003

6-thioguanine--efficacy and safety in chronic active Crohn's disease.

BACKGROUND: : Azathioprine and mercaptopurine are commonly used in chronic active Crohn's disease. They share the disadvantage of a delayed onset of action and potentially serious side-effects, and are metabolized to thioguanine nucleotides which are thought to be the active metabolites. The direct use of 6-thioguanine may offer a more rapid and safer alternative. We conducted an open prospective study to investigate the efficacy and safety of 6-thioguanine in chronic active Crohn's disease. METHODS: : Thirty-seven patients with chronic active Crohn's disease and a Crohn's disease activity index of > 150 were enrolled in this study. Inclusion criteria were steroid dependence (n = 19), steroid refractoriness (n = 9) and/or intolerance (n = 16) or refractoriness (n = 6) to azathioprine. Patients were treated with 40 mg/day of 6-thioguanine for 24 weeks; a dose escalation to 80 mg was allowed at week 12. Remission was defined as a Crohn's disease activity index of < 150 associated with a decrease of > 70 points; response was defined as a decrease of > 70 points in the Crohn's disease activity index. RESULTS: : In the intention-to-treat analysis, 13 of 37 patients achieved remission (35%). Twelve of these 13 patients achieved remission after 4 weeks. Fifty-seven per cent of patients (21/37) achieved a response. The mean Crohn's disease activity index decreased from 284 +/- 74 to 153 +/- 101. 6-Thioguanine was more effective in azathioprine-intolerant than in azathioprine-refractory patients. Twelve of 16 patients intolerant to azathioprine tolerated 6-thioguanine. Adverse events included phototoxicity, pancreatitis, headache, nausea, alopecia, arthralgia, minor infections and reversible elevation of transaminases. Six patients required discontinuation of medication, two because of leucopenia. CONCLUSIONS: : In this patient group with chronic active Crohn's disease, 6-thioguanine appeared to be effective with acceptable short-term toxicity, but long-term controlled trials are clearly needed to further define its role.

Adult↗
PubMed2003

Defensin pattern in chronic gastritis: HBD-2 is differentially expressed with respect to Helicobacter pylori status.

BACKGROUND/AIMS: Recent reports have suggested that Helicobacter pylori infection induces the mucosal antibiotic peptide human beta defensin 2 (HBD-2). Therefore, the present study investigated mRNA and peptide expression of four different defensins in the upper gastrointestinal tract in patients with H pylori positive and negative chronic gastritis. MATERIALS/METHODS: Biopsies from the oesophagus to the duodenum were taken during routine gastroscopy in 71 individuals. Total RNA was extracted and the reverse transcription polymerase chain reaction was performed with primers for human defensins 5 and 6 (HD-5/6) or HBD-1 and HBD-2. Paraffin wax embedded tissue from gastric resections was tested for HD-5, HBD-1, and HBD-2 by immunohistochemistry. RESULTS: Helicobacter pylori colonisation was associated with an increased percentage of positive biopsies with respect to HBD-2 in the corpus (p < 0.05). Helicobacter pylori had no impact on the gastric expression of HD-5 and HBD-1, whereas HD-6 was increased in the fundus. The abundant expression of alpha defensins in the duodenum and beta defensins in the oesophagus served as a positive control in each individual. Immunohistochemical analysis confirmed the presence of the HD-5, HBD-1, and HBD-2 peptides in gastric resection specimens. CONCLUSIONS: The recently described induction of HBD-2 upon H pylori infection was confirmed in a clinical setting of chronic gastritis. This phenomenon may be mediated by components of the pathogen itself or may occur secondary to immune events in chronic inflammation.

Adult↗
PubMed2002

Innate immunity and colonic inflammation: enhanced expression of epithelial alpha-defensins.

Human alpha-defensins contribute to local intestinal host defense as part of innate immunity and may be of major relevance in microbial infection and chronic inflammatory bowel disease. The objective was to investigate human defensin 5 and 6 (HD-5, HD-6) mRNA expression by RT-PCR from colonic biopsies and peptide expression by immunohistochemistry from colonic resections under basal and inflammatory conditions. Both alpha-defensins were induced by proinflammatory cytokines in cell culture. HD-5 mRNA expression was enhanced in both idiopathic and nonidiopathic inflammatory states of the large bowel [32% of control vs 73% of unspecific colitis, 69% of Crohn's disease (CD) and 73% of ulcerative colitis (UC)], whereas HD-6 was specifically related to CD and UC (14% in controls vs 20% in unspecific coltis, 49% in CD and 42% in UC). Immunohistochemistry confirmed the presence of HD-5 in colonic epithelium. Antimicrobial peptides in the colon may be of importance in maintaining the mucosal barrier and controlling microbial invasion in inflammatory bowel diseases.

Caco-2 Cells↗
PubMed2002

Alterations in pulmonary function in inflammatory bowel disease are frequent and persist during remission.

OBJECTIVES: Information on the occurrence and frequency of pulmonary involvement in patients with inflammatory bowel disease (IBD) is inconsistent. The aim of this prospective study was to determine the frequency and type of pulmonary dysfunction in patients with IBD. METHODS: Sixty-six patients with IBD (35 with Crohn's disease [CD] and 31 with ulcerative colitis [UC]) and 30 control patients were investigated with respect to the following pulmonary function tests: forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC), Tiffeneau value (FEV1/IVC), and lung CO transfer capacity (D(LCO)). Disease activity in IBD patients was assessed by the CD activity index for CD and the Truelove index for UC, respectively. Smoking habits and medication were documented in every patient. RESULTS: Fourteen of 36 CD patients (39%) and 14 of 31 UC patients (45%) but only one of the controls exhibited at least one pathological (<80% of predicted value) pulmonary function test. In both CD and UC lung function tests were significantly decreased in comparison to the control group. This could be shown for FEV1 (-14% of predicted value in CD and -17% in UC, p < 0.01), IVC (-10% in CD and -12% in UC, p < 0.05), and DLCO (-20% in CD and -31% in UC, p < 0.01) without significant differences between both disease entities. The impairment of pulmonary function tests was more pronounced in patients with active disease than in those with inactive disease (FEV1, 81.4% vs 93.4% predicted, p < 0.02; IVC, 84.4% vs 93.7%, p < 0.05; DLCO, 80.4% vs 95.8%, ns). CONCLUSIONS: IBD patients show significantly decreased lung function tests in comparison to healthy controls. The impairment in active disease exceeded that during remission.

Adult↗
PubMed2001

[Sweet syndrome and erythema nodosum in ulcerative colitis, refractory to steroids: successful treatment with tacrolimus].

BACKGROUND: Inflammatory bowel disease is accompanied by cutaneous manifestations in about 10% of cases. Erythema nodosum and pyoderma gangraenosum are most frequently observed, which often subside on treatment of the underlying disease. CASE REPORT: A 30-year-old male with a history of long-standing ulcerative colitis experienced an acute attack despite treatment with azathioprine. Further he noticed dull red, elevated and tender maculae on the forelegs. A disseminated and papulosquamous exanthema arose on the back of the trunk and the upper extremities without pruritus. Well-being was compromised and blood sampling revealed an inflammatory response. High-dose steroids with antibiotics were without benefit until they were combined with tacrolimus, an immunosuppressive agent acting similar to ciclosporin. Remission occurred rapidly and the skin lesions resolved. Six months later the patient is currently still in remission and developed no signs of recurrent exanthema. CONCLUSION: The cutaneous lesions are thought to be related to ulcerative colitis and were classified as erythema nodosum and Sweet syndrome. This is the first report on the successful use of tacrolimus in steroid-refractory ulcerative colitis with extraintestinal cutaneous involvement.

Adult↗
PubMed2001

Minimal renal dysfunction in inflammatory bowel disease is related to disease activity but not to 5-ASA use.

BACKGROUND: Conflicting data exist about proteinuria in inflammatory bowel diseases. It is still unclear whether the occurrence of proteinuria in inflammatory bowel disease patients is an extra-intestinal manifestation of disease or the result of adverse effects to medication, especially to aminosalicylates (ASA). METHODS: A total of 95 patients (51 with Crohn's disease and 44 with ulcerative colitis) were enrolled in the study. Disease activity was assessed by Crohn's Disease Activity Index (CDAI) or the Truelove index, respectively. Urine was collected over 24 h and protein excretion of specific marker proteins for tubular (alpha 1-microglobulin-alpha 1-MG) and glomerular (albumin-Alb, Immunoglobulin G-IgG) dysfunction was measured using a highly sensitive immunoluminometric assay. RESULTS: Out of 51 Crohn's disease patients, 20 showed elevated urinary alpha 1-MG. The amount of alpha 1-MGuria was strongly correlated to the CDAI (r=0.6, P < 0.001). Only four Crohn's disease patients showed slightly elevated values for glomerular proteins in urine. Similar results were obtained for ulcerative colitis: whereas only two ulcerative colitis patients showed albuminuria, tubular proteinuria was detected in 28 out of 44 ulcerative colitis patients. Proteinuria was strongly dependent on disease activity (P < 0.01) but was not related to ASA treatment. CONCLUSIONS: Proteinuria of tubular marker proteins occurs in the majority of inflammatory bowel disease patients and is related to disease activity rather than to ASA treatment. Tubular proteinuria seems to reflect a renal extra-intestinal manifestation of inflammatory bowel disease and may serve as a new relevant marker of disease activity.

Adolescent↗
PubMed2000

The pancreas and inflammatory bowel diseases.

This article reviews the literature and gives an overview on prevalence and possible explanations for pancreatic involvement in inflammatory bowel diseases (IBD). IBD patients have a markedly elevated risk for developing acute pancreatitis as well as pancreatic insufficiency. Multiple potential causes for pancreatitis in IBD patients exist. In the majority of cases acute pancreatitis appears to be related to drug side effects or local structural complications rather than a true extraintestinal manifestation of IBD. Nevertheless, some cases of acute pancreatitis remain unexplained. Prevalence of chronic pancreatitis in IBD patients also seems to be relatively high. However, etiology of pancreatic duct changes and/or the occurrence of exocrine insufficiency remain unclear. In most cases chronic pancreatitis is clinically unapparent, although in some patients it may be accompanied by clinically relevant exocrine insufficiency.

Acute Disease↗