Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis

Objective: To investigate the relationship between serum trough infliximab levels and clinical response to infliximab treatment in patients with rheumatoid arthritis (RA). Methods: Disease activity and serum trough infliximab levels before and 2, 6, and 14 weeks after initiation of infliximab treatment at a dose of 3 mg/kg in a cohort of 105 patients with RA were assessed. Serum trough infliximab levels in responders and non-responders were compared. Additionally, the clinical responses of patients with high, intermediate, and low serum trough infliximab levels at 14 weeks were compared. Results: After 14 weeks of treatment non-responders had lower serum trough levels of infliximab than responders ( median (interquartile range) 0.5 (0.2 - 2.2) v 3.6 (1.4 - 8.2) mg/l; p <0.01)). Patients with low serum trough infliximab levels at 14 weeks had significantly less improvement in the 28 joint count Disease Activity Score (DAS28) score than patients with intermediate or high serum trough infliximab levels at 14 weeks. Pretreatment C reactive protein (CRP) levels correlated negatively with serum trough infliximab levels at 14 weeks after the start of treatment ( Spearman rank correlation r(s) = -.43, p <0.001). Conclusion: Serum trough levels of infliximab correlate with the clinical response to treatment with infliximab and pretreatment CRP levels. This study indicates that patients with high pretreatment CRP levels might benefit from higher dosages of infliximab or shorter dosing interval

Sequential evacuation strategy for multiple rooms toward the same means of egress

This paper examines different evacuation strategies for systems where several rooms evacuate trough the same means of egress, using microscopic pedestrian simulation.As a case study, a medium-rise office building is considered. It was found that the standard strategy, whereby the simultaneous evacuation of all levels is performed, can be improved by a sequential evacuation, beginning with the lowest floor and continuing successively with each one of the upper floors after a certain delay. The importance of the present research is that it provides the basis for the design and implementation of new evacuation strategies and alarm systems that could significantly improve the evacuation of multiple rooms trough a common means of escape.Comment: 8 pages, 4 figure

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were &lt; 9.0, 9.0-12.9, 12.9-22.8, and &gt; 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p &lt; 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).ConclusionsWe identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity

Analysis of DNA-Damage Response to ionizing radiation in serum-shock synchronized human fibroblasts.

Many aspects of cellular physiology, including cellular response to genotoxic stress, are related to the circadian rhythmicity induced by the molecular clock. The current study investigated if the cellular response to DNA damage is in relation to endogenous expression levels of the PER2 protein, a key component of the molecular regulatory system that confers rhythmicity in mammalian cells. Human normal fibroblasts (CCD-34Lu) were subjected to serum shock to induce circadian oscillations of the PER2 protein and then irradiated with \u3b3- rays at times corresponding to the trough and peak expression of the PER2 protein. To better examine cellular response to DNA damage, the experiments performed in this study were carried out in non-proliferating CCD-34Lu fibroblasts in order to maintain the cell and circadian cycles separated while they were being exposed to genotoxic stress. Study results demonstrated that clonogenic cell survival, double-strand break repair kinetics, and TP53 protein levels were affected in the cells irradiated at the trough than in those irradiated at peak expression of the PER2 protein

Coulomb-enhanced resonance transmission of quantum SINIS junctions

Coherent charge transfer through a ballistic gated SINIS junction is mediated by the resonant tunneling via the Andreev states. Extra charge accommodated on the Andreev levels partially compensates the charge induced by the gate voltage preserving the electron wavelength and maintaining the resonance conditions in a broad range of gate voltages. As a result, the transparency of the junction as well as the supercurrent trough it can be substantially increased as compared to the zero-Coulomb case

Low plasma cefepime levels in critically ill septic patients: pharmacokinetic modelling indicates improved troughs with revised dosing

The pharmacokinetics of a 2-g bolus of cefepime were measured in critically ill patients with normal renal function. Variable and low trough plasma drug concentrations were found, and 8 of 10 patients had levels below the MIC at which 50% of the isolates are inhibited for Pseudomonas aeruginosa. Computer simulations predicted that continuous infusion and shorter dosing intervals would increase trough levels

Viewpoint on handling anti-TNF failure in psoriasis

An association among the occurrence of antidrug antibodies (ADAs), diminished trough serum drug levels (TSDLs) and non-response or loss of response has been described for several tumor necrosis factor alpha (TNF) blocking agents in a variety of diseases, including psoriasis. In a series of ten psoriasis patients with primary or secondary failure, or adverse reactions during anti-TNF therapy, we measured ADAs and TSDLs in patient serum using radioimmunoassay and ELISA, respectively. By proposing a treatment algorithm derived from research in this field, we show that measuring ADAs and TSDLs in psoriasis patients provides a more structured approach to clinical decision making for psoriasis patients who fail anti-TNF therapy

Isoniazid concentrations in hair and plasma area-under-the-curve exposure among children with tuberculosis.

We measured hair and plasma concentrations of isoniazid among sixteen children with tuberculosis who underwent personal or video-assisted directly observed therapy and thus had 100% adherence. This study therefore defined typical isoniazid exposure parameters after two months of treatment among fully-adherent patients in both hair and plasma (plasma area under the concentration-time curve, AUC, estimated using pharmacokinetic data collected 0, 2, 4, and 6 hours after drug administration). We found that INH levels in hair among highly-adherent individuals did not correlate well with plasma AUC or trough concentrations, suggesting that each measure may provide incremental and complementary information regarding drug exposure in the context of TB treatment