Determination of ADMET properties of substituted-piperidine-3-carboxamide derivatives with potential use in the treatment of Crohn's disease

BackgroundEsophageal Crohn’s disease is reported as a rare manifestation, although its prevalence may be underestimated because upper endoscopies are not routinely performed in asymptomatic adults. Tofacitinib, an oral janus kinase inhibitor, is a new biologic that has shown promise in the treatment of ulcerative colitis and may be effective in the treatment of Crohn’s disease according to phase 2 trials. We report the first case of esophageal Crohn’s disease successfully treated with tofacitinib in a patient with worsening symptoms despite maintenance therapy with a tumor necrosis factor-α inhibitor.Case presentationA 67-year-old Caucasian woman presented with new dysphagia and had findings of esophageal Crohn’s disease on endoscopy. The dosage of her current biologic therapy—adalimumab—was increased in frequency, without improvement. Our patient was started on tofacitinib and demonstrated an improvement in symptoms, with a repeat endoscopy showing resolution of the previous lesions.ConclusionEsophageal Crohn’s disease is likely underdiagnosed but is an important consideration in a patient with new symptoms of dysphagia and known Crohn’s disease. Tofacitinib, while a novel agent, could have a role in the treatment of esophageal Crohn’s disease that does not improve with intensification of the current biologic therapy. It provides a different mechanism in patients who become refractory to maintenance therapy.

Use of infliximab in the treatment of Crohn's disease in children and adolescents

In 1988, Greenberg and colleagues published a large randomized controlled trial to address whether bowel rest could lead to improved disease activity in patients with active Crohn's disease. The results of this study provide substantial evidence that bowel rest is not necessary to achieve remission in patients with active Crohn's disease receiving nutrition support. Before this study, great controversy existed about the use of nutrition support and bowel rest in the treatment of active Crohn's disease because of a limited number of conflicting studies providing evidence for and against its application. The results of the publication by Greenberg et al are fundamental because they helped to settle this important argument. Furthermore, this pivotal paper changed the clinical guidelines for the use of nutrition support in the management of active Crohn's disease. Since the publication of this pivotal article, many developments in the field of nutrition and in the treatment of Crohn's disease have helped validate and further its results. Subsequent studies and debate center on the use of enteral nutrition as primary treatment in patients with active Crohn's disease. Data regarding the efficacy, composition, and overall role of adult enteral nutrition in the management of Crohn's disease are presented. This article revisits the Greenberg paper and discusses some of these innovations in nutrition.

Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2)

The present study aimed to identify hub genes associated with the treatment and control of active and inactive Crohn's disease (CD). Differentially expressed genes (DEGs) were identified in normal, active CD, and inactive CD samples from GSE95095 dataset. Intersection genes screened by Venn diagram in DEGs. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted on the intersection genes. The protein-protein interaction (PPI) network was used to screen of hub gene. The expression and mRNA levels of CXCL12 in CD and ROC curves in GSE95095 dataset. Signaling pathways of hub genes and their correlation with immune cells were analyzed by gene set enrichment analysis (GSEA), EPIC, and ESTIMATE, respectively. Finally, immunohistochemistry (IHC) and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) were used to detect the expression of the hub gene in normal, inactive, and active CD tissues. In GSE95095 dataset, CXCL12 was identified as the most hub gene by limma analysis, Venn diagram and A protein-protein interaction (PPI) network. CXCL12 expression was highest in active CD (p < 0.001) followed by inactive CD (p < 0.01). Subsequently, it was validated through IHC and RT-PCR in normal intestinal mucosal, active CD, and inactive CD. CXCL12 was overexpressed in active and inactive CD (IHC: p < 0.001 and RT-PCR: p < 0.001, respectively). CXCL12 expression in active CD was determined via analysis with receiver operating characteristic (ROC) curves. The specificity and sensitivity were 0.875 and 0.625, respectively, the accuracy was 72.92%, the area under the curve (AUC) was 0.780, and the 95% confidence interval (CI) was in the range of 0.648-0.912. CXCL12 expression was closely correlated with various immune cells. CXCL12 is overexpressed in active CD and is closely correlated with various immune cells. We propose that CXCL12 as a potential target genes for the treatment and management of both active and inactive CD.

ABSTRACTCrohn’s disease is a chronic, or long lasting inflammatory disease in the gastrointestinal (GI) tract. Most commonly, Crohn’s disease affects the small intestine and the beginning of the large intestine. Treatment for Crohn’s disease usually involves drug therapy or, in certain cases, surgery. Several side effects develop from the use of drugs. A case with Crohn’s disease refractory to 5-ASA, corticosteroid and azathioprine treatments who developed breast carcinoma following infliximab treatment is being presented in this report. Case: SE, aged 44 years, presented to our polyclinic with weight loss, abdominal pain and flatulence. The patient had no response to mesalazine, steroid and azathioprine therapy. Upon identifying inflammatory stricture with abdominal MR, the medicines the patient has been using was discontinued and anti-TNF alpha (infliximab) treatment was initiated after receiving the consent of the patient. At 3rd month of treatment, the patient detected a small mass at the left breast. Mastectomy was performed and axillary lymph nodes were resected.Because breast cancer was detected following infliximab treatment in this case, we believe that a breast examination (physical examination, mammary USG) must be performed in female patients prior to infliximab therapy.How to cite this article: Goral V, Unsal B, Sivrikoz ON. A Case of Breast Cancer Following Infliximab Treatment for Treatment-Refractory Crohn’s Disease. Euroasian J Hepato-Gastroenterol 2014;4(2): 104-106.

Crohn’s fistula: current concepts in management

It has been suggested that cyclosporin A might be of some benefit to patients with Crohn's disease. The clinical response and side-effects of cyclosporin A in Crohn's disease are described in a series of 13 adults. The majority of patients had ileal disease and all but one were started on an initial oral dose of 15 mg/kg per day. Duration of treatment ranged from 3 to 42 weeks. Of the 13 patients, 6 showed a response to therapy; the remainder showed no response or deteriorated. The commonest side-effect was hyperaesthesia, but one patient developed nephrotoxicity and one developed hepatotoxicity. Significant drug malabsorption occurred in one case. The side-effects were dose dependent and reversible. Cyclosporin A may have a part to play in the treatment of resistant Crohn's disease, and in our hands has been associated with a 46 per cent response rate; however, the precise role of cyclosporin A in the management of Crohn's disease awaits further study.

Budesonide, although only topically active, is effective in the treatment of Crohn's disease. This study was performed to compare the clinical efficacies of budesonide and prednisolone in relation to the activation status of circulating leukocytes. Twenty-four patients with active Crohn's disease were randomized to treatment with either budesonide or 6-methylprednisolone. Clinical response was monitored by the Crohn's disease activity index, C-reactive protein, and orosomucoid. Expression of CD25 and CD71 on T cells and CD64 on neutrophils was determined by flow cytometry. The release of TNF-alpha and IL-1beta by peripheral blood mononuclear cells was measured by ELISA. After 2 wk of treatment a clinical response was observed in both groups, but it was more accentuated in patients treated with prednisolone. At baseline an upregulation of CD71 and CD64, but not CD25, was found in active patients. Prednisolone significantly decreased the expression of CD64 and the release of TNF-alpha and IL-1beta, but did not alter the expression of CD25 and CD71. Budesonide treatment failed to exert any effect on circulating leukocytes. The inability of budesonide to downregulate activated circulating leukocytes may contribute to the somewhat lower clinical efficacy of this topical steroid in the treatment of active Crohn's disease.

Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor

This Month in Gastroenterology

In a randomized multicenter trial the efficacy of treatment of active Crohn's disease by means of a liquid defined formula diet (DFD) was tested and compared with a combination of 6-methyl-prednisolone and sulfasalazine. A total of 95 patients participated in the study. By the end of 6 weeks, among 44 patients randomized to drug treatment, 32 showed improvement of the Crohn's disease activity index (CDAI) as compared with 21 of 51 patients receiving oral DFD (p less than 0.05). The proportion of withdrawals in the DFD group (29 of 51) was sevenfold higher than in the drug group (4 of 44). However, most patients (20 of 29) receiving DFD withdrew because of the unpalatability of the liquid diet. Analysis of patients in each group who finished the study showed equal effectiveness of DFD and the drug regimen. In these subsets of patients the CDAI decreased from 280.8 +/- 90.6 to 151.7 +/- 86.5 (DFD) and from 263.7 +/- 86.3 to 129.3 +/- 63.7 (drug), respectively. Improvement of inflammation factors was similar in both groups at the end of the study, although improvement was delayed in the DFD group. In conclusion, our data show a superiority of the drug combination over DFD in the treatment of Crohn's disease under the conditions of this trial. The results do suggest, however, that DFD offers a therapeutic alternative to prednisolone and sulfasalazine in a subgroup of patients, which has to be closer characterized in further studies.

The mechanisms by which elemental diets induce remission in patients with Crohn's disease is unknown, but it has been suggested that improvement in nutritional state may play a part. We assessed sequential changes in disease activity (clinical and laboratory indices and faecal excretion of indium-111-labelled leucocytes) and nutritional status (anthropometry, body composition variables), hepatic secretory proteins (albumin, pre-albumin, transferrin), and trace elements (iron, magnesium, copper, zinc) during treatment of acute Crohn's disease with an elemental diet. Disease activity indices improved significantly by 2 weeks and were maintained at 4 weeks of treatment. There was a significant increase in pre-albumin at 4 weeks and an increase in serum iron and a decrease in serum copper during the study period. The changes occurring in the measures of nutrition did not correlate significantly with the changes in disease activity. The fact that changes in disease activity appear to precede any detectable changes in nutritional state, it suggests that the beneficial action of elemental diet in patients with active Crohn's disease is not due to an improvement in nutritional status.

Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in Inflammatory Bowel Disease

Vitamin D has immune-regulatory functions in experimental colitis, and low vitamin D levels are present in Crohn's disease. To assess the effectiveness of vitamin D3 treatment in Crohn's disease with regard to improved disease course. We performed a randomized double-blind placebo-controlled trial to assess the benefits of oral vitamin D3 treatment in Crohn's disease. We included 108 patients with Crohn's disease in remission, of which fourteen were excluded later. Patients were randomized to receive either 1200 IU vitamin D3 (n = 46) or placebo (n = 48) once daily during 12 months. The primary endpoint was clinical relapse. Oral vitamin D3 treatment with 1200 IU daily increased serum 25OHD from mean 69 nmol/L [standard deviation (s.d.) 31 nmol/L] to mean 96 nmol/L (s.d. 27 nmol/L) after 3 months (P < 0.001). The relapse rate was lower among patients treated with vitamin D3 (6/46 or 13%) than among patients treated with placebo (14/48 or 29%), (P = 0.06). Oral supplementation with 1200 IE vitamin D3 significantly increased serum vitamin D levels and insignificantly reduced the risk of relapse from 29% to 13%, (P = 0.06). Given that vitamin D3 treatment might be effective in Crohn's disease, we suggest larger studies to elucidate this matter further. ClinicalTrial.gov(NCT00122184).