Complexity of intravenous iron nanoparticle formulations: implications for bioequivalence evaluation

Intravenous iron formulations are a class of complex drugs that are commonly used to treat a wide variety of disease states associated with iron deficiency and anemia. Venofer® (iron–sucrose) is one of the most frequently used formulations, with more than 90% of dialysis patients in the United States receiving this formulation. Emerging data from global markets outside the United States, where many iron–sucrose similars or copies are available, have shown that these formulations may have safety and efficacy profiles that differ from the reference listed drug. This may be attributable to uncharacterized differences in physicochemical characteristics and/or differences in labile iron release. As bioequivalence evaluation guidance evolves, clinicians should be educated on these potential clinical issues before a switch to the generic formulation is made in the clinical setting.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139940/1/nyas13461.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139940/2/nyas13461_am.pd

Quantification of Lipoteichoic Acid in Hemodialysis Patients With Central Venous Catheters

Hemodialysis patients with central venous catheters (CVCs) have chronic systemic inflammation, the source of which may be related to intraluminal bacterial biofilm. There is currently no non-invasive method to adequately evaluate intraluminal biofilm. Lipoteichoic acid (LTA) is a Gram-positive bacterial cell wall component that is spontaneously shed. The purpose of this study was to determine whether LTA could be quantified in biological samples and to evaluate potential relationships to markers of inflammation. Heparin-locked catheter aspirate was drawn from both the arterial and venous ports of each CVC prior to dialysis initiation. Venous blood from the dialysis circuit was collected 30 min after dialysis initiation. LTA was quantified in aspirate and plasma. Key markers of inflammation (interleukin-6, and hepcidin) and endothelial dysfunction (soluble vascular endothelial cadherin) were also determined in plasma samples. Catheter aspirate and systemic blood samples were obtained from 40 hemodialysis patients. The median (range) duration of catheter use was 130 (20–1635) days. Unexpectedly, median (range) plasma LTA concentrations (ng/mL) were significantly higher than catheter aspirate LTA concentrations [3.93 (0.25–15) vs. 2.38 (0.1–8.1), respectively, p = 0.01] in the majority (70%) of patients. Area under the receiver operator characteristic (ROC) curve showed good potential prognostic value of catheter aspirate LTA predicting systemic LTA concentrations with an area under the curve of 0.815 (95% CI, 0.68–0.95). A significant correlation was found between LTA and serum ferritin (r = 0.32, p = 0.04), however, there were no significant correlations between LTA and the other inflammation biomarkers assessed. LTA is quantifiable in aspirate and plasma of hemodialysis patients with CVCs and warrants further investigation to determine potential clinical application to intraluminal biofilm evaluation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Assessment of literacy and numeracy skills related to non-steroidal anti-inflammatory drug labels

Background: Non-steroidal anti-inflammatory drugs are widely used and have a potential for over-the-counter misuse. Limited health literacy is associated with poor health outcomes. Identification of new strategies to assess literacy and numeracy could be useful in targeting effective education initiatives. Objective: To characterize numeracy and literacy skills related to non-steroidal anti-inflammatory drug labels in primary care patients. Methods: Patients were recruited and consented over an 8-month period after their regular primary care visit. Demographic information was collected and two instruments were administered to assess literacy and numeracy skills: (1) a medication label literacy instrument focused on non-steroidal anti-inflammatory drugs (MedLit-NSAID) and (2) a general healthy literacy-screening tool, the Newest Vital Sign. Two questions on the MedLit-NSAID instrument evaluated understanding of the Food and Drug Administration medication guide for non-steroidal anti-inflammatory drugs and the Food and Drug Administration approved over-the-counter label. Results: A total of 145 patients were enrolled. Mean MedLit-NSAID and Newest Vital Sign scores were 6.8 (scale range 0–8) and 4.2 (scale range 0–6), respectively. Higher education level was associated with higher scores for both tools (p ⩽ 0.05). Total MedLit-NSAID scores on average were higher in females compared with males (6.5 vs 6, p = 0.05). Patients with decreased kidney function (n = 18) had significantly lower MedLit-NSAID scores (p ⩽ 0.05). Test–retest scores were not significantly different for MedLit-NSAID (p = 0.32). The correlation between the tools was 0.54 and internal consistency MedLit-NSAID was 0.61. Conclusion: A medication information focused instrument provided specific information to assess health literacy related to non-steroidal anti-inflammatory drug labels. This information could be utilized to develop patient education initiatives for medication label comprehension

Impact of hemodialysis on the concentrations of sodium and potassium during infusion of sodium thiosulfate using an In Vitro hemodialysis model.

INTRODUCTION:The purpose of this study was to evaluate the impact of hemodialysis on the concentrations of sodium and potassium in the blood when a 25 g dose of sodium thiosulfate injection is infused over 60 minutes in combination with hemodialysis. METHODS:Sodium thiosulfate (25 g) was prepared by diluting 100 mL of 250 mg/mL Sodium Thiosulfate Injection with 800 mL of 5% dextrose. This was added to the circulating blood surrogate solution at a rate of 15 mL/minute using an infusion pump of an in vitro model of dialysis machine. Serial samples were collected before the administration of the sodium thiosulfate solution, after 15 minutes, 30 minutes, and 60 minutes of infusion from pre-and post-dialyzer ports in both the dialysate circuit and the extracorporeal circuit. FINDINGS:The concentration of sodium thiosulfate in pre-dialyzer and post-dialyzer samples of the circulating blood surrogate solution peaked at 30 minutes and 15 minutes, respectively and then remained relatively unchanged during the remainder of the infusion. Mean sodium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 103.2 ± 12.2, 114.2 ± 18.8, 117.2 ± 7.5, 93.5 ± 5.9 at 0, 15, 30, and 60 minutes, respectively (p = 0.248). Mean potassium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 1.4 ± 0.3, 1.6 ± 0.3, 1.5 ± 0.1, 1.2 ± 0.1 at 0, 15, 30, and 60 minutes, respectively (p = 0.365). Sodium and potassium concentrations in dialysate increased marginally after exposure to the dialyzer. DISCUSSION:Our study demonstrates that neither potassium nor sodium accumulated in circulating blood surrogate solution when a dose of sodium thiosulfate was infused in conjunction with hemodialysis

Lipoteichoic Acid from <em>Staphylococcus aureus</em> Induces Lung Endothelial Cell Barrier Dysfunction: Role of Reactive Oxygen and Nitrogen Species

<div><p>Tunneled central venous catheters (TCVCs) are used for dialysis access in 82% of new hemodialysis patients and are rapidly colonized with Gram-positive organism (e.g. <em>Staphylococcus aureus</em>) biofilm, a source of recurrent infections and chronic inflammation. Lipoteichoic acid (LTA), a cell wall ribitol polymer from Gram-positive organisms, mediates inflammation through the Toll-like receptor 2 (TLR2). The effect of LTA on lung endothelial permeability is not known. We tested the hypothesis that LTA from <em>Staphylococcus aureus</em> induces alterations in the permeability of pulmonary microvessel endothelial monolayers (PMEM) that result from activation of TLR2 and are mediated by reactive oxygen/nitrogen species (RONS). The permeability of PMEM was assessed by the clearance rate of Evans blue-labeled albumin, the activation of the TLR2 pathway was assessed by Western blot, and the generation of RONS was measured by the fluorescence of oxidized dihydroethidium and a dichlorofluorescein derivative. Treatment with LTA or the TLR2 agonist Pam₍₃₎CSK₍₄₎ induced significant increases in albumin permeability, IκBα phosphorylation, IRAK1 degradation, RONS generation, and endothelial nitric oxide synthase (eNOS) activation (as measured by the p-eNOS^ser1177:p-eNOS^thr495 ratio). The effects on permeability and RONS were effectively prevented by co-administration of the superoxide scavenger Tiron, the peroxynitrite scavenger Urate, or the eNOS inhibitor L-NAME and these effects as well as eNOS activation were reduced or prevented by pretreatment with an IRAK1/4 inhibitor. The results indicate that the activation of TLR2 and the generation of ROS/RNS mediates LTA-induced barrier dysfunction in PMEM.</p> </div

How to select a nanosimilar

Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability