Assessment of Vedolizumab Disease-Drug-Drug Interaction Potential in Patients With Inflammatory Bowel Diseases.

Disease-drug-drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti-inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well-established positive benefit-risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4ß-hydroxycholesterol-to-cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.

Biofilm forming ability of Sphingomonas paucimobilis isolated from community drinking water systems on plumbing materials used in water distribution.

Sphingomonas paucimobilis, an oligotroph, is well recognized for its potential for biofilm formation. The present study explored the biofilm forming ability of a strain isolated from municipal drinking water on plumbing materials. The intensity of biofilm formation of this strain on different plumbing materials was examined by using 1 × 1 cm2 pieces of six different pipe materials, i.e. polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), aluminium (Al), copper (Cu) and rubber (R) and observing by staining with the chemical chromophore, Calcofluor. To understand whether biofilm formation occurs under flow through conditions, a laboratory-scale simulated distribution system, comprised of the above materials was fabricated. Biofilm samples were collected from the designed system at different biofilm ages (10, 40 and 90 hours old) and enumerated. The results indicated that the biofilm formation occurred on all plumbing materials with Cu and R as exceptions. The intensity of biofilm formation was found to be maximum on PVC followed by PP and PE. We also demonstrated the chemical chromophore (Calcofluor) successfully for rapid and easy visual detection of biofilms, validated by scanning electron microscope (SEM) analysis of the plumbing materials. Chlorination has little effect in preventing biofilm development.

First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70.

PURPOSE: The study evaluated the safety, tolerability, and pharmacokinetics of BMS-936561, a fully human monoclonal antibody-drug conjugate targeting CD70 cell-surface protein. METHODS: Eligible patients had ECOG performance status 0-2 and received ≤3 prior chemotherapy regimens. An initial accelerated titration design enrolling one patient per dose level was followed by 3 + 3 dose escalation with the first observation of a grade ≥2 adverse event (AE). We tested escalating doses of BMS-936561 (0.5, 1, 2, 4, 8, 15 mg/kg) administered every 21 days in a 42 day cycle for a maximum of 17 cycles. Pharmacokinetic samples were collected in cycle 1. RESULTS: A total of 26 patients enrolled; 16 and 10 for the escalation and expansion cohorts, respectively. Median age was 63 years (48-74); 18 males and 25 Caucasians. There was no defined MTD per protocol, but a DLT of grade 3 hypersensitivity was recorded in 2 of 16 (13%) subjects at the highest dose of 15 mg/kg. The most frequent AEs were: fatigue (85%), nausea (54%), and decreased appetite (39%). Delayed toxicities (facial edema and pleural/pericardial effusions) occurred in 6 of 16 (38%) subjects at the 15 mg/kg dose. PK analysis showed a dose-proportional increase in active drug levels with increasing doses. There was disease stabilization in 18 of 26 patients (69%) without correlation with received dose. CONCLUSIONS: BMS-936561 is well tolerated over a wide range of doses in patients with advanced ccRCC and B-NHL. The 8 mg/kg dose was the highest best tolerated dose and the recommended dose for future studies.

AU-rich elements in the 3'-UTR regulate the stability of the 141 amino acid isoform of parathyroid hormone-related protein mRNA.

We demonstrated previously that parathyroid hormone-related protein (PTHrP) 1-141 mRNA is the least stable of three isoforms and is the only isoform that is stabilized by TGF-ß. In order to understand how PTHrP mRNA is stabilized by TGF-ß, we first sought to elucidate the mechanism(s) that are responsible for the instability of PTHrP isoform 1-141 mRNA. The 3'-UTR of isoform 1-141 contains four AU-rich elements (AREs), which are known to mediate mRNA degradation. We utilized a luciferase reporter system to test whether these four AREs are responsible for the short half-life of PTHrP 1-141 mRNA. Our results demonstrated that ARE elements in the 3'-UTR of PTHrP 1-141 mRNA play a significant role in regulation of the stability of the mRNA. It is known that AREs mediate their effects on mRNA stability through a number of ARE-binding proteins that recruit the exosome, a complex of exonucleases that degrades the mRNA. We identified tristetraproline (TTP) as an RNA-binding protein that may be involved in ARE-mediated degradation of PTHrP 1-141 mRNA.

Impact of aprotinin and renal function on mortality: a retrospective single center analysis.

BACKGROUND: An estimated up to 7% of high-risk cardiac surgery patients return to the operating room for bleeding. Aprotinin was used extensively as an antifibrinolytic agent in cardiac surgery patients for over 15 years and it showed efficacy in reducing bleeding. Aprotinin was removed from the market by the U.S. Food and Drug Administration after a large prospective, randomized clinical trial documented an increased mortality risk associated with the drug. Further debate arose when a meta-analysis of 211 randomized controlled trials showed no risk of renal failure or death associated with aprotinin. However, only patients with normal kidney function have been studied. METHODS: In this study, we look at a single center clinical trial using patients with varying degrees of baseline kidney function to answer the question: Does aprotinin increase odds of death given varying levels of preoperative kidney dysfunction? RESULTS: Based on our model, aprotinin use was associated with a 3.8-fold increase in odds of death one year later compared to no aprotinin use with p-value = 0.0018, regardless of level of preoperative kidney dysfunction after adjusting for other perioperative variables. CONCLUSIONS: Lessons learned from our experience using aprotinin in the perioperative setting as an antifibrinolytic during open cardiac surgery should guide us in testing future antifibrinolytic drugs for not only efficacy of preventing bleeding, but for overall safety to the whole organism using long-term clinical outcome studies, including those with varying degree of baseline kidney function.