Intravascular tissue reactions induced by various types of bioabsorbable polymeric materials: correlation between the degradation profiles and corresponding tissue reactions

Several different bioabsorbable polymeric coil materials are currently used with the goal of improving treatment outcomes of endovascular embolization of intracranial aneurysms. However, little is known about the correlation between polymer degradation profiles and concomitant tissue responses in a blood vessel. The authors describe in vitro degradation characteristics of nine different polymeric materials and their corresponding tissue responses induced in rabbit carotid arteries. Mass loss and molecular weight loss of nine commercially available bioabsorbable sutures were evaluated in vitro up to16 weeks. The same nine materials, as well as platinum coils, were implanted into blind-end carotid arteries (n = 44) in rabbits, and their tissue reactions were evaluated histologically 14 days after the implantation. Five of the nine polymers elicited moderate to strong tissue reactions relative to the remaining materials. While polymer mass loss did not correlate with their histologic findings, polymers that showed a faster rate of molecular weight loss had a tendency to present more active tissue reactions such as strong fibrocellular response around the implanted material with a moderate inflammatory cell infiltration. Maxon exhibited the fastest rate of molecular weight loss and poly-l-lactic acid the slowest. The rate of molecular weight loss may be an important factor that is associated with the degree of bioactivity when bioabsorbable polymers are implanted into blood vessels. For further quantitative analysis, additional experiments utilizing established aneurysm models need to be conducted

Exposure–response relationship of AMG 386 in combination with weekly paclitaxel in recurrent ovarian cancer and its implication for dose selection

To characterize exposure-response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.A population pharmacokinetic model of AMG 386 (N = 141) was developed and applied in an exposure-response analysis using data from patients (N = 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve [AUC(ss)]) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.There was a trend toward increased PFS with increased AUC(ss) (hazard ratio [HR] for each one-unit increment in AUC(ss), 0.97; P = 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC(ss) ≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC(ss) < 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC(ss) and grade ≥ 3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC(ss) ≥ 9.6 mg h/mL in > 90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR [15 mg/kg vs. placebo], 0.56).Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies

Characterization of different FAD-dependent glucose dehydrogenases for possible use in glucose-based biosensors and biofuel cells

In this study, different flavin adenine dinucleotide (FAD)-dependent glucose dehydrogenases (FADGDHs) were characterized electrochemically after “wiring” them with an osmium redox polymer [Os(4,4′-dimethyl-2,2′-bipyridine)2(PVI)10Cl]+ on graphite electrodes. One tested FADGDH was that recently discovered in Glomerella cingulata (GcGDH), another was the recombinant form expressed in Pichia pastoris (rGcGDH), and the third was a commercially available glycosylated enzyme from Aspergillus sp. (AspGDH). The performance of the Os-polymer “wired” GDHs on graphite electrodes was tested with glucose as the substrate. Optimal operational conditions and analytical characteristics like sensitivity, linear ranges and current density of the different FADGDHs were determined. The performance of all three types of FADGDHs was studied at physiological conditions (pH 7.4). The current densities measured at a 20 mM glucose concentration were 494 ± 17, 370 ± 24, and 389 ± 19 μA cm−2 for GcGDH, rGcGDH, and AspGDH, respectively. The sensitivities towards glucose were 2.16, 1.90, and 1.42 μA mM−1 for GcGDH, rGcGDH, and AspGDH, respectively. Additionally, deglycosylated rGcGDH (dgrGcGDH) was investigated to see whether the reduced glycosylation would have an effect, e.g., a higher current density, which was indeed found. GcGDH/Os-polymer modified electrodes were also used and investigated for their selectivity for a number of different sugars

Pharmacokinetics and Exposure–Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

Introduction: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. Methods: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure–efficacy and exposure–safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. Results: Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. Conclusion: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. Funding: Janssen Research & Development

Mapping Molecular Orientation with Phase Sensitive Vibrationally Resonant Sum-Frequency Generation Microscopy

We demonstrate a phase sensitive, vibrationally resonant sum-frequency generation (PSVR-SFG) microscope that combines high resolution, fast image acquisition speed, chemical selectivity, and phase sensitivity. Using the PSVR-SFG microscope, we generate amplitude and phase images of the second-order susceptibility of collagen I fibers in rat tail tendon tissue on resonance with the methylene vibrations of the protein. We find that the phase of the second-order susceptibility shows dependence on the effective polarity of the fibril bundles, revealing fibrous collagen domains of opposite orientations within the tissue. The presence of collagen microdomains in tendon tissue may have implications for the interpretation of the mechanical properties of the tissue. [Image: see text