Lower Risk of Recurrence with a Higher Induction Dose of Mesalazine and Longer Duration of Treatment in Ulcerative Colitis: Results from the Dutch, Non-Interventional, IMPACT Study

Background & Aims: The dose and duration of mesalazine treatment for ulcerative colitis (UC) is a potentially important determinant of effectiveness, with evidence suggesting that continuing the induction dose for 6-12 months may improve outcomes; however, real-world data are lacking. We assessed mesalazine use in Dutch clinical practice, including how differences in dose and duration affected UC outcomes.Methods: Adults with mild-to-moderate UC who received oral prolonged-release mesalazine de novo or had a dose escalation for an active episode were followed for 12 months in this non-interventional study (ClinicalTrials.gov identifier: NCT02261636). The primary endpoint was time from start of treatment to dose reduction (TDR). Secondary endpoints included recurrence rate, adherence, and work productivity.Results: In total, 151 patients were enrolled, of whom 108 (71.5%) were newly diagnosed with UC. The majority (120; 79.5%) received a dose of >= 4 g/day. Nearly one-third (48; 31.8%) underwent dose reduction, with mean TDR being 8.3 months. Disease extent and endoscopic appearance did not influence duration of induction therapy, while TDR increased with higher baseline UCDAI scores. TDR was longer in patients without (mean 8.8 months) than with (4.1 months) recurrence, although not significantly (p=0.09). Patients on >= 4 g/day had a significantly lower chance of recurrence versus those on 2-6 months vs 3-6 months: 0.19 (95%CI: 0.08-0.46); p= 4 g/day [0.15 (0.06-0.40) vs 0.26 (0.01-11.9) for 2-= 4 g/day) and longer duration of treatment (>6 months) was associated with a lower recurrence risk.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Identification of Two Different 14-α Sterol Demethylase-Related Genes ( cyp51A

Two cyp51-related genes (cyp51A and cyp51B) encoding 14-α sterol demethylase-like enzymes were identified in the opportunistic human pathogen Aspergillus fumigatus. PCR amplification using degenerate oligonucleotides based on conserved areas of cytochrome P450 demethylases of other filamentous fungi and yeasts allowed the cloning and sequencing of two different homologue genes in A. fumigatus. Southern analysis confirmed that both genes hybridized to distinct genomic loci and that both are represented as single copies in the genome. Comparison of the deduced Cyp51A and Cyp51B proteins with the CYP51 proteins from Penicillium italicum, Aspergillus nidulans, Erysiphe graminis, Uncinula necator, Botrytis cinerea, Ustilago maydis, Cryptococcus neoformans, Candida albicans, Saccharomyces cerevisiae, Candida tropicalis, and Candida glabrata showed that the percentages of identity of the amino acid sequences (range, 40 to 70%) were high enough to consider Cyp51A and Cyp51B to be members of the fungal CYP51 family. Fragments from both genes were also cloned from other Aspergillus spp. (A. flavus, A. nidulans, and A. terreus). Phylogenetic analysis showed that, at least in the most pathogenic species of Aspergillus, there are two fungal CYP51 proteins. This is the first report of the existence of two homologue genes coding for 14-α sterol demethylase in the fungal kingdom. This finding could provide insights into the azole resistance mechanisms operating in fungi. The primers used here may be useful molecular tools for facilitating the cloning of novel 14-α sterol demethylase genes in other filamentous fungi