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Introduction: Only a few reports are available on the population pharmacokinetic (PK) analysis of linezolid and its main metabolites. Therefore, we investigated the population PK of linezolid and its metabolites in adult patients treated with intravenous linezolid to identify the causative factors affecting pharmacokinetics, and evaluated the relationship between the parent compound and major metabolites PNU‐142300 and PNU‐142586. Methods: Population PK analysis was performed using medical data collected from patients who were treated with intravenous linezolid (600 mg twice daily). We examined the impact of covariate candidates such as demographic characteristics and laboratory parameters. Simulations using the final model were investigated and used to estimate the plasma concentrations, trough concentrations (Cmin), and area under the curve (AUC) of linezolid and its metabolites, and the metabolite‐to‐parent ratios for Cmin and AUC were used to assess the accumulation of metabolites over linezolid. Results: A total of 82 plasma concentrations from 23 patients were analyzed. The volume of distribution was estimated to be 47.1 L, assuming that linezolid and its metabolites were the same. The total clearance (CL) of linezolid, and CLs of PNU‐142300 and PNU‐142586 were influenced by creatinine clearance (CLcr), with population mean CLs of 3.86, 7.27, and 13.54 L/h, respectively. The Cmin and AUCs of linezolid and its metabolites and the ratios of metabolites per linezolid were predicted to increase exponentially with decreasing renal function. Conclusion: We developed the first population PK model in which CLcr was incorporated as a covariate in the CL of linezolid and its metabolites. Using the final model, it was possible to predict the plasma concentration, Cmin, and AUC appropriately. The model was found to be a potentially useful tool for future studies on optimal dosing and toxicity analysis. [ABSTRACT FROM AUTHOR]

A copper‐mediated radioiodination using aryl boronic precursors is attracting attention as a solution to oxidative iododestannylation and nickel‐mediated radioiodination drawbacks. The copper‐mediated radiolabeling method allows radioiodination at room temperature with stable aryl boronic precursors without preparing complex starting materials or reagents and can be performed in a reaction vessel exposed to air. This method has good potential in radiochemistry; however, studies on the scope of copper‐mediated radioiodination through boronic precursors are insufficient. In particular, few reports have demonstrated the effect of protecting groups on radiolabeling efficiency. Therefore, the effect of the protecting group of aryl boronic acids on the copper‐mediated radioiodination was investigated. In addition, this method, which does not require heating, is expected to be useful for direct radiolabeling of peptides. Thus, we attempted direct radioiodination of c(RGDyk) as an example. The resulting radioiodination method was well tolerated in various substrates and was unaffected by the pinacol ester‐type protecting group. Also, c(RGDyk) was labeled with 125I via copper‐mediated radioiodination using an aryl boronic acid precursor. The reaction time and yield were improved, compared with the indirect method. Furthermore, the large difference in polarity between the boronic acid precursor and the radiolabeled compound facilitated purification. [ABSTRACT FROM AUTHOR]

Using an in vitro random screening of small-molecule compounds, we discovered cis-diamminedichloroplatinum( II) (cisplatin), an anticancer agent, as a potential inhibitor of collagen fibril-formation. The inhibitory effect was found only when cisplatin was dissolved in dimethylsulphoxide ( DMSO), indicating that the active species were cisplatin derivatives formed in the DMSO solution. The cisplatin derivatives inhibited the formation of collagen fibrils in vitro without affecting the triple-helical conformation of the collagen molecules. Incubation with the cisplatin solution in DMSO also inhibited in situ deposition of collagen fibrils in a human umbilical vein endothelial cell (HUVEC) culture. In addition, the derivatization of cisplatin in DMSO abolished the cytotoxicity of the original compound. The platinum complex was further revealed to interact with specific sites on the collagen triple helix, and the binding sites were suggested to contain His and/or Met residues. Mass spectrometry analysis of the cisplatin solution in DMSO and a structure-activity relationship study strongly suggested that the active compound is [Pt( NH3)2(Cl)( DMSO)]+. This platinum complex will be useful for investigating molecular mechanisms of collagen self-assembly and for drug development for the treatment of fibrotic diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Collagen-model peptides composed of (X-Y-Gly)n sequences were used to study the triple helical structure of collagen. We report the stability of these collagen-like peptides in biological fluids, and their pharmacokinetics including distribution, metabolism, and excretion in animals. A typical collagen-model peptide, H-(Pro-Hyp-Gly)10-OH, was found to be extremely stable in the plasma and distributed mainly in the vascular blood space, and was eliminated through glomerular filtration in the kidneys. Triple helical peptides of (X-Y-Gly)n sequences were quantitatively recovered from the urine of rats after intravenous injection regardless of the differences in peptide net charge between −3 and +6 per triple helix. In contrast, the renal clearance became less efficient when the number of triplet repeats (n) was 12 or more. We also demonstrated the application of a collagen-like triple helical peptide as a novel drug carrier in the blood with a high urinary excretion profile. We further demonstrated that a collagen-like triple helical peptide conjugated to a spin probe, PROXYL, has the potential to evaluate the redox status of oxidative stress-induced animals in vivo. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 705-713, 2013. [ABSTRACT FROM AUTHOR]

Exposure to asbestos is a risk for malignant mesothelioma (MM) in humans. Among the commercially used types of asbestos (chrysotile, crocidolite, and amosite), the carcinogenicity of chrysotile is not fully appreciated. Here, we show that all three asbestos types similarly induced MM in the rat peritoneal cavity and that chrysotile caused the earliest mesothelioma development with a high fraction of sarcomatoid histology. The pathogenesis of chrysotile-induced mesothelial carcinogenesis was closely associated with iron overload: repeated administration of an iron chelator, nitrilotriacetic acid, which promotes the Fenton reaction, significantly reduced the period required for carcinogenesis; massive iron deposition was found in the peritoneal organs with high serum ferritin; and homozygous deletion of the CDKN2A/2B/ARF tumour suppressor genes, the most frequent genomic alteration in human MM and in iron-induced rodent carcinogenesis, was observed in 92.6% of the cases studied with array-based comparative genomic hybridization. The induced rat MM cells revealed high expression of mesoderm-specific transcription factors, Dlx5 and Hand1, and showed an iron regulatory profile of active iron uptake and utilization. These data indicate that chrysotile is a strong carcinogen when exposed to mesothelia, acting through the induction of local iron overload. Therefore, an intervention to remove local excess iron might be a strategy to prevent MM after asbestos exposure. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

As reactive oxygen species (ROS) are involved in the pathogenesis of various diseases, superoxide dismutase (SOD) and its mimetic complexes have been intensively studied. Recently, we found that Cu2(aspirinate)4 (Cu2(asp)4) has both in vitro and in vivo antioxidative activities. We investigated the suppressive effect of Cu2(asp)4 on ROS generation in the skin of hairless mice that were orally administered Cu2(asp)4 and followed by UVA exposure. The results were compared with those obtained from mice that were orally administered Cu(salicylate)2 (Cu(sal)2) or Cu(acetate)2, (Cu(ace)2) and followed by UVA exposure. After confirming that Cu2(asp)4 suppressed ROS generation in the skin, we measured both SOD activity and metallothionein (MT) and SOD protein levels in the whole proteins extracted from the skin of ICR mice that were orally administered Cu(II) compounds. The Cu2Zn2-SOD activity was enhanced by the administration of Cu(II) compounds; however, no alterations in the protein levels of MT and SOD were observed. Metallokinetics of the paramagnetic Cu(II) species in the circulating blood of rats, as estimated by electron spin resonance (ESR), revealed that among the Cu(II) compounds, the residence time of the Cu(II) species from Cu2(asp)4 was the longest. On the basis of these results, we conclude that Cu2(asp)4 is an orally potent antioxidative compound that suppresses ROS generation in the skin. The residence time of Cu(II) in the blood and the enhanced SOD activity in the skin following the oral administration of Cu2(asp)4 support this conclusion. Here, we propose that Cu2(asp)4 may be used to protect the skin against ROS generation. [ABSTRACT FROM AUTHOR]

Although the formation of reactive oxygen species (ROS) in the skin induced by the ultraviolet (UV) light has been shown to lead to many cutaneous disorders, skin cancer and photoageing, the mechanism and distribution of ROS generation has not yet been definitively determined. In the present study, we examined the distribution of UVA-induced ROS in the skin of live hairless mice, using our proposed in vivo imaging chemiluminescent (CL) method to detect ROS combined with a CL probe ( cypridina hilgendorfii luciferin analogue; CLA) and tape stripping (TS) technique. The CL intensities in the skin of live hairless mice were confirmed to significantly increase by UVA exposure. When TS was conducted five times in a maximum level after CL measurement following UVA exposure and subsequent CLA application, CL intensities due to UVA-induced ROS generation in the residual skin decreased to 10% of the original levels; and those in the stripped skin on each tape decreased in the stripped order such as 52%, 16%, 11%, 6% and 5%. Next, CLA was applied and then CL intensities were measured in the residual skin after advance 1, 3 and 5 tape strippings, and CL intensities due to ROS were detected primarily in the outer layer of the skin. On the basis of these results, we concluded that ROS induced by UVA exposure occurs and distributes in the outermost layer of the stratum corneum. [ABSTRACT FROM AUTHOR]

The article presents a distinct screening strategy for protection against UV-induced skin damage with the combination of human skin equivalent model (HSEM) and 8-OHdG immunohistochemistry. It discuses the real-time chemiluminescent imaging to detect reactive oxygen species in HSEM after UVB exposure. It describes the method as an alternative to animal experiments and focuses on emerging concepts in fragile genomic sites for oxidative stress and UV-specific DNA base modifications.