Highlights • Subtherapeutic voriconazole (VCZ) concentrations are common in clinical practice. • The CYP2C19*17 allele is associated with increased VCZ metabolism. • VCZ doses to achieve target ...levels are higher in CYP2C19*17 carriers. • CYP2C19 genotyping can predict VCZ exposure/dose to achieve effective levels.
Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured
in vitro
to produce spermatozoa for ...assisted reproductive technology. A complete
in vitro
spermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency. Steroid hormones are essential for the progression of spermatogenesis, the aim of this study was to investigate steroidogenesis and steroid signaling in organotypic cultures. Histological, RT-qPCR, western blot analyses, and steroid hormone measurements were performed on
in vitro
cultured mouse prepubertal testicular tissues and age-matched
in vivo
controls. Despite a conserved density of Leydig cells after 30 days of culture (D30), transcript levels of adult Leydig cells and steroidogenic markers were decreased. Increased amounts of progesterone and estradiol and reduced androstenedione levels were observed at D30, together with decreased transcript levels of steroid metabolizing genes and steroid target genes. hCG was insufficient to facilitate Leydig cell differentiation, restore steroidogenesis, and improve sperm yield. In conclusion, this study reports the failure of adult Leydig cell development and altered steroid production and signaling in tissue cultures. The organotypic culture system will need to be further improved before it can be translated into clinics for childhood cancer survivors.
Purpose/Aims: Infectious keratitis is a major cause of visual impairment and blindness worldwide. Common difficulties in treating fungal keratitis prompt new therapeutic possibilities. In this study, ...intrastromal voriconazole and posaconazole, and topical posaconazole were tested for their potential to obtain therapeutic cornea concentrations.
Materials and Methods: Pharmacokinetics of triazole intracorneal/eye drop administration was studied in rats. Sixty-two rats were treated either by voriconazole or posaconazole. Twenty-nine and 33 rats received intrastromal injection of voriconazole solution (1 μl, 10 mg/ml) and posaconazole solution (1 μl, 18 mg/ml), respectively, administered under microscopic examination with a 32 gauge needle in the left cornea. Posaconazole (1.8% solution) eye drops were used. Cornea and plasma concentrations were determined using 2D HPLC separation and tandem MS, at 30 min, 3 h, 6 h, 24 h, 48 h, 72 h, and 144 h (6 days) post-intrastromal injection. The entire rat cornea was used for chromatography analyses.
Results: In anesthetized rats, single intracorneal injection resulted, after 30 min, in respectively, >300 ng/mg and >260 ng/mg cornea concentrations, dropping to low levels within hours, while staying low in plasma. The effect of hourly posaconazole eye drops resulted in >10 ng/mg cornea concentration, which was maintained with instillations every 2 and then every 4 h.
Conclusion: Our results show that there is little interest of intrastromal triazole administration due to the short duration of high cornea concentrations obtained after intracorneal injection. Posaconazole eye drops maintain therapeutic cornea concentrations in rats and could be used to treat severe infectious keratitis.
Both unmodified cupric oxide (CuO) nanoparticles and those functionalized with a bi-functional coupling agent methacryloxypropyl-trimethoxysilane (MPS) were used to fabricate vinyl-ester resin ...polymeric nanocomposites. The nanoparticle functionalization was observed to have a significant effect on the physical properties of the cupric oxide filled vinyl-ester resin nanocomposite. Thermal degradation study by thermo-gravimetric analysis (TGA) showed the increased thermo-stability in the functionalized-nanoparticle-filled vinyl-ester resin nanocomposites as compared with the unmodified-nanoparticle-filled counterparts. The more uniform particle dispersion and the chemical bond between nanoparticle and vinyl-ester resin were found to contribute to the increased thermal stability and enhanced tensile strength.
Silicon carbide reinforced polyurethane nanocomposites were fabricated by a facile surface-initiated-polymerization (SIP) method. The particle loading was tuned to up to 35
wt% without any obvious ...shrinkage and breakage as compared with the conventional direct mixing method. An increased thermal stability of the composites was observed with the addition of the silicon carbide nanoparticles under thermo-gravimetric analysis (TGA). Tensile strength was observed to increase dramatically with the increase of the particle loading. Both the uniform particle dispersion and the strong chemical bonding between the nanoparticles and the polymer–matrix contributed to the enhanced thermal stability and improved mechanical properties.
The pharmacokinetics and metabolism of the l-threo isoleucine thiazolidide dipeptidyl peptidase IV inhibitor, di-2S,3S-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate (ILT-threo) and its allo ...stereoisomer (ILT-allo) were evaluated in rats, dogs, and monkeys. Both compounds were well absorbed (>80%) in all species, and most of the dose (>60%) was recovered in urine. Metabolites identified in all species included a sulfoxide (M1), a sulfone (M2), and a carbamoyl glucuronide (M3). For both compounds, parent drug had moderate systemic clearance in rats and dogs ( approximately 20-35 ml/min/kg in both species) and lower clearance in monkeys ( approximately 6-9 ml/min/kg). In rats, M1 was present in systemic circulation in concentrations similar to that of parent drug, whereas in dogs and monkeys, exposures to M1 were higher than for parent drug. In dogs, exposures to the sulfoxide metabolite were approximately 2 to 3 times higher after administration of ILT-allo than after administration of ILT-threo. Carbamoyl glucuronidation was an important biotransformation pathway in dogs. Circulating levels of M3 were significant in the dog, and present only in trace levels in rats and monkeys. M3 could be produced in in vitro systems in a NaHCO3 buffer under a CO2-saturated atmosphere and in the presence of UDP-glucuronic acid and alamethicin.
This study demonstrates the construction of a multifunctional composite structure capable of energy storage in addition to load bearing. These structures were assembled and integrated within the ...confines of a multifunctional structural composite in order to save weight and space. Carbon fiber reinforced plastic (CFRP) composites were laminated with energy storage all-solid-state thin-film lithium cells. The processes of physically embedding all-solid-state thin-film lithium energy cells into carbon fiber reinforced plastics (CFRPs) and the approaches used are reviewed. The effects of uniaxial tensile loading on the embedded structure are investigated. The mechanical, electrical, and physical aspects of energy harvesting and storage devices incorporated into composite structures are discussed. Embedding all-solid-state thin-film lithium energy cells into CFRPs did not significantly alter the CFRP mechanical properties (yield strength and Young's modulus). The CFRP embedded energy cells performed at baseline charge/discharge levels up to a loading of about 50% of the ultimate CFRP uniaxial tensile rupture loading.
Chemo‐induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first‐line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, ...hematological safety profile, and impact on survival following the initiation of either the brand‐name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m2 per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed‐effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand‐name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo‐induced thrombocytopenia was more frequent in the generic group: 19.6% 95% CI 8.7‐30.5% vs 3.1% 0‐6.6%, P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ‐induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 1.21‐2.8, P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand‐name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results.
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