Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

International audienceThe pregnane-X-receptor (PXR) is master gene overseeing detoxification of wide number of xenobiotics and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-regulated in patients with inflammatory bowel diseases (IBD). Rifaximin, is a non absorbable antibiotic endowed with a PXR agonistic activity. In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of Tumor necrosis factor (TNF)-α on expression of PXR and PXR-related genes. Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification. Exposure to TNFα reduces the expression of PXR mRNA as well as expression of its target genes. This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. Finally, exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism. In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes involved in the metabolism and excretion of xenobiotics and antagonized the effects of TNFα in intertsinal epithelial cells and colon biopsies. These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria

New polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations.

Cryst. polymorphous forms of the rifaximin (INN) antibiotic named rifaximin  and rifaximin  useful in the prodn. of medicinal prepns. contg. rifaximin for oral and topical use and obtained by means of a crystn. process carried out by hot-dissolving the raw rifaximin in Et alc. and by causing the crystn. of the product by addn. of water at a determinate temp. and for a determinate period of time, followed by a drying carried out under controlled conditions until reaching a settled water content in the end product, are the object of the invention

The impact of integration of a multidetector computed tomography annulus area sizing algorithm on outcomes of transcatheter aortic valve replacement: a prospective, multicenter, controlled trial

ObjectivesThis study prospectively investigated the impact of integration of a multidetector computed tomography (MDCT) annular area sizing algorithm on transcatheter aortic valve replacement (TAVR) outcomes.BackgroundAppreciation of the 3-dimensional, noncircular geometry of the aortic annulus is important for transcatheter heart valve (THV) sizing.MethodsPatients being evaluated for TAVR in 4 centers underwent pre-procedural MDCT. Recommendations for balloon-expandable THV size selection were based on an MDCT sizing algorithm with an optimal goal of modest annulus area oversizing (5% to 10%). Consecutive patients who underwent TAVR with the algorithm (MDCT group) were compared with consecutive patients without the algorithm (control group). The primary endpoint was the incidence of more than mild paravalvular regurgitation (PAR), and the secondary endpoint was the composite of in-hospital death, aortic annulus rupture, and severe PAR.ResultsOf 266 patients, 133 consecutive patients underwent TAVR (SAPIEN XT THV) in the MDCT group and 133 consecutive patients were in the control group. More than mild PAR was present in 5.3% (7 of 133) of the MDCT group and in 12.8% (17 of 133) in the control group (p = 0.032). The combined secondary endpoint occurred in 3.8% (5 of 133) of the MDCT group and in 11.3% (15 of 133) of the control group (p = 0.02), driven by the difference of severe PAR.ConclusionsThe implementation of an MDCT annulus area sizing algorithm for TAVR reduces PAR. Three-dimensional aortic annular assessment and annular area sizing should be considered for TAVR

Impact of Morbid Obesity and Obesity Phenotype on Outcomes After Transcatheter Aortic Valve Replacement

There is a paucity of outcome data on patients who are morbidly obese (MO) undergoing transcatheter aortic valve replacement. We aimed to determine their periprocedural and midterm outcomes and investigate the impact of obesity phenotype. Consecutive patients who are MO (body mass index, ≥40 kg/m 2, or ≥35 kg/m 2 with obesity-related comorbidities; n=910) with severe aortic stenosis who underwent transcatheter aortic valve replacement in 18 tertiary hospitals were compared with a nonobese cohort (body mass index, 18.5-29.9 kg/m 2, n=2264). Propensity-score matching resulted in 770 pairs. Pre-transcatheter aortic valve replacement computed tomography scans were centrally analyzed to assess adipose tissue distribution; epicardial, abdominal visceral and subcutaneous fat. Major vascular complications were more common (6.6% versus 4.3%; P =0.043) and device success was less frequent (84.4% versus 88.1%; P =0.038) in the MO group. Freedom from all-cause and cardiovascular mortality were similar at 2 years (79.4 versus 80.6%, P =0.731; and 88.7 versus 87.4%, P =0.699; MO and nonobese, respectively). Multivariable analysis identified baseline glomerular filtration rate and nontransfemoral access as independent predictors of 2-year mortality in the MO group. An adverse MO phenotype with an abdominal visceral adipose tissue:subcutaneous adipose tissue ratio ≥1 (VAT:SAT) was associated with increased 2-year all-cause (hazard ratio [HR], 3.06; 95% CI, 1.20-7.77; P =0.019) and cardiovascular (hazard ratio, 4.11; 95% CI, 1.06-15.90; P =0.041) mortality, and readmissions (HR, 1.81; 95% CI, 1.07-3.07; P =0.027). After multivariable analysis, a (VAT:SAT) ratio ≥1 remained a strong predictor of 2-year mortality (hazard ratio, 2.78; P =0.035). Transcatheter aortic valve replacement in patients who are MO has similar short- and midterm outcomes to nonobese patients, despite higher major vascular complications and lower device success. An abdominal VAT:SAT ratio ≥1 identifies an obesity phenotype at higher risk of adverse clinical outcomes

Transcatheter Aortic Valve Replacement in Pure Native Aortic Valve Regurgitation

Background Limited data exist about safety and efficacy of transcatheter aortic valve replacement (TAVR) in patients with pure native aortic regurgitation (AR). Objectives This study sought to compare the outcomes of TAVR with early- and new-generation devices in symptomatic patients with pure native AR. Methods From the pure native AR TAVR multicenter registry, procedural and clinical outcomes were assessed according to VARC-2 criteria and compared between early- and new-generation devices. Results A total of 331 patients with a mean STS score of 6.7 ± 6.7 underwent TAVR. The early- and new-generation devices were used in 119 patients (36.0%) and 212 patients (64.0%), respectively. STS score tended to be lower in the new-generation device group (6.2 ± 6.7 vs. 7.6 ± 6.7; p = 0.08), but transfemoral access was more frequently used in the early-generation device group (87.4% vs. 60.8%; p < 0.001). Compared with the early-generation devices, the new-generation devices were associated with a significantly higher device success rate (81.1% vs. 61.3%; p < 0.001) due to lower rates of second valve implantation (12.7% vs. 24.4%; p = 0.007) and post-procedural AR â\u89¥ moderate (4.2% vs. 18.8%; p < 0.001). There were no significant differences in major 30-day endpoints between the 2 groups. The cumulative rates of all-cause and cardiovascular death at 1-year follow-up were 24.1% and 15.6%, respectively. The 1-year all-cause mortality rate was significantly higher in the patients with post-procedural AR â\u89¥ moderate compared with those with post-procedural AR â\u89¤ mild (46.1% vs. 21.8%; log-rank p = 0.001). On multivariable analysis, post-procedural AR â\u89¥ moderate was independently associated with 1-year all-cause mortality (hazard ratio: 2.85; 95% confidence interval: 1.52 to 5.35; p = 0.001). Conclusions Compared with the early-generation devices, TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR. In patients with pure native AR, significant post-procedural AR was independently associated with increased mortality