PubMed | Virology., Toxicology. and King's College
Type: Journal Article | Journal: Medical mycology | Year: 2016
Triazole antifungal drugs are widely used for the prophylaxis and treatment of invasive fungal disease (IFD). Efficacy may depend on attaining minimum effective plasma concentrations. The aim of this study was to ascertain the proportion of samples in which the recommended concentrations were achieved in patients given these drugs in relation to outcome. In-patients prescribed standard doses of fluconazole, itraconazole solution, posaconazole suspension, or oral voriconazole for at least one week were studied. Pre-dose serum triazole concentrations were measured using validated methods. There were 359 samples from 90 patients. The median (range) number of samples per patient was 3 (1-13), and the median (range) fluconazole, itraconazole, posaconazole (prophylaxis), posaconazole (treatment), and voriconazole serum concentrations were 5.64 (0.11-18), 0.57 (0-5.3), 0.31 (0.02-2.5), 0.65 (0.02-2.5), and 0.95 (0.10-5.4) mg/l, respectively. The number of samples in which the recommended pre-dose concentrations were achieved was 98 (54%), 9 (20%), 2 (18%), and 29 (49%) for itraconazole, posaconazole (>0.7mg/l prophylaxis), posaconazole (treatment), and voriconazole, respectively. No significant differences were detected in the median triazole trough concentrations between patients with proven/probable IFD compared to those with no evidence of IFD. However, itraconazole was not detected in 10 samples (7 patients). The small number of patients who achieved the recommended trough posaconazole concentrations may explain the high rate of break-through IFD observed in patients prescribed this drug. Except for fluconazole, the number of patients prescribed standard doses of triazoles who achieved recommended trough triazole concentrations was low. The prospective use of serum triazole measurements assay may have improved outcomes with itraconazole, posaconazole, and with voriconazole.
Fuchs T.C.,Toxicology |
AAPS Journal | Year: 2011
The detection of acute kidney injury (AKI) and the monitoring of chronic kidney disease (CKD) is becoming more important in industrialized countries. Because of the direct relation of kidney damage to the increasing age of the population, as well as the connection to other diseases like diabetes mellitus and congestive heart failure, renal diseases/failure has increased in the last decades. In addition, drug-induced kidney injury, especially of patients in intensive care units, is very often a cause of AKI. The need for diagnostic tools to identify drug-induced nephrotoxicity has been emphasized by the ICH-regulated agencies. This has lead to multiple national and international projects focusing on the identification of novel biomarkers to enhance drug development. Several parameters related to AKI or CKD are known and have been used for several decades. Most of these markers deliver information only when renal damage is well established, as is the case for serum creatinine. The field of molecular toxicology has spawned new options of the detection of nephrotoxicity. These new developments lead to the identification of urinary protein biomarkers, including Kim-1, clusterin, osteopontin or RPA-1, and other transcriptional biomarkers which enable the earlier detection of AKI and deliver further information about the area of nephron damage or the underlying mechanism. These biomarkers were mainly identified and qualified in rat but also for humans, several biomarkers have been described and now have to be validated. This review will give an overview of traditional and novel tools for the detection of renal damage. © 2011 American Association of Pharmaceutical Scientists.
PubMed | IONIS Pharmaceuticals, Toxicology, Structural Biology and Medicinal Chemistry
Type: | Journal: Molecular therapy. Nucleic acids | Year: 2016
Triantennary N-acetyl galactosamine (GalNAc3) is a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors. Conjugation with GalNAc3 via a trishexylamino (THA)-C6 cluster significantly enhances antisense oligonucleotide (ASO) potency. Herein, the biotransformation, disposition, and elimination of the THA cluster of ION-681257, a GalNAc3-conjugated ASO currently in clinical development, are investigated in rats and monkey. Rats were administered a single subcutaneous dose of (3)H-radiolabeled ((3)H placed in THA) or nonradiolabeled ION-681257. Mass balance included radiometric profiling and metabolite fractionation with characterization by mass spectrometry. GalNAc3-conjugated ASOs were extensively distributed into liver. The THA-C6 triantenerrary GalNAc3 conjugate at the 5-end of the ASO was rapidly metabolized and excreted with 25.671.635% and 71.664.17% of radioactivity recovered in urine and feces within 48 hours postdose. Unchanged drug, short-mer ASOs, and linker metabolites were detected in urine. Collectively, 14 novel linker associated metabolites were discovered including oxidation at each branching arm, initially by monooxidation at the -position followed by dioxidation at the -arm, and lastly, tri and tetra oxidations on the two remaining -arms. Metabolites in bile and feces were identical to urine except for oxidized linear and cyclic linker metabolites. Enzymatic reaction phenotyping confirmed involvement of N-acetyl--glucosaminidase, deoxyribonuclease II, alkaline phosphatase, and alcohol + aldehyde dehydrogenases on the complex metabolism pathway for THA supplementing in vivo findings. Lastly, excreta from monkeys treated with ION-681257 revealed the identical series as observed in rat. In summary, our findings provide an improved understanding of GalNAc3-conjugated-ASO metabolism pathways which facilitate similar development programs.
Coen M.,Imperial College London |
Goldfain-Blanc F.,Toxicology |
Rolland-Valognes G.,Institute Of Recherches Servier |
Walther B.,DMPK |
And 4 more authors.
Journal of Proteome Research | Year: 2012
Galactosamine (galN) is widely used as an in vivo model of acute liver injury. We have applied an integrative approach, combining histopathology, clinical chemistry, cytokine analysis, and nuclear magnetic resonance (NMR) spectroscopic metabolic profiling of biofluids and tissues, to study variability in response to galactosamine following successive dosing. On re-challenge with galN, primary non-responders displayed galN-induced hepatotoxicity (induced response), whereas primary responders exhibited a less marked response (adaptive response). A systems-level metabonomic approach enabled simultaneous characterization of the xenobiotic and endogenous metabolic perturbations associated with the different response phenotypes. Elevated serum cytokines were identified and correlated with hepatic metabolic profiles to further investigate the inflammatory response to galN. The presence of urinary N-acetylglucosamine (glcNAc) correlated with toxicological outcome and reflected the dynamic shift from a resistant to a sensitive phenotype (induced response). In addition, the urinary level of glcNAc and hepatic level of UDP-N-acetylhexosamines reflected an adaptive response to galN. The unique observation of galN-pyrazines and altered gut microbial metabolites in fecal profiles of non-responders suggested that gut microfloral metabolism was associated with toxic outcome. Pharmacometabonomic modeling of predose urinary and fecal NMR spectroscopic profiles revealed a diverse panel of metabolites that classified the dynamic shift between a resistant and sensitive phenotype. This integrative pharmacometabonomic approach has been demonstrated for a model toxin; however, it is equally applicable to xenobiotic interventions that are associated with wide variation in efficacy or toxicity and, in particular, for prediction of susceptibility to toxicity. © 2012 American Chemical Society.
Kozlovic G.,Kozlovic Winery |
Jeromel A.,University of Zagreb |
Maslov L.,University of Zagreb |
Pollnitz A.,Toxicology |
Orlic S.,University of Zagreb
Food Chemistry | Year: 2010
In order to improve Malvazija from Istria wine quality, we used two types of barrels: oak (of French and Croatian origin) and acacia (of Croatian origin). After 12 months ageing period all of the wines were analysed chemically and sensorially. Results showed marked differences between oak and acacia aged wines, especially in simple volatile phenol and oak lactones concentrations. During the ageing period a significant increase in furfural, 5-methylfurfural, guaiacol, eugenol and trans-eugenol was noticed. Results pointed out the importance of choosing the right barrels (oak or acacia) and time of leaving the wine in the barrels to achieve the desired goal. The highest rated wines were made in acacia barrels. © 2009 Elsevier Ltd. All rights reserved.
PubMed | Toxicology, University of Barcelona and University of Murcia
Type: Journal Article | Journal: Transplantation proceedings | Year: 2015
The aim of this work was to evaluate the CYP3A5:CYP3A5*1/CYP3A5*3 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients.This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n= 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use ofa TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele (minor-allele) was analyzed for correlation with the tacrolimus dose-normalized ratio during the 3 months after transplantation.The following observations were obtained in the population studied: (1) Frequency of the minor allele*1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A5*1/*3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele*1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P< .05).The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1-polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype.
Fuchs T.C.,Toxicology |
Biomarkers in Medicine | Year: 2011
The assessment of kidney damage is a challenge and must incorporate assessment of the functional capacity of the kidney, as well as a comprehensive understanding of the kidney's role. Multiple parameters have been used for many years to measure renal functionality to assess renal damage. It is astonishing that, beside histopathology, the most common traditional parameters are serum based. However, urine is also used to obtain additional information regarding the health status of the kidneys. Since 2008, several novel urinary protein biomarkers have been qualified by the US FDA and the European Medicines Agency in conjunction with the Predictive Safety Testing Consortium in a specially developed qualification process. Subsequently, the Pharmaceuticals and Medical Devices Agency accepted the qualification of these seven urinary biomarkers. This review will give an overview of the state-of-the-art detection based on urinary biomarkers, which will enhance toxicological research in the future. In addition, the qualification process that leads to acceptance of these biomarkers will be described because of its uniqueness and importance for the field of biomarker research. © 2011 Future Medicine Ltd.
European Journal of Oncology | Year: 2010
Cosmetic products are very lightly regulated in the United States, even though cosmetic products may contain hazardous ingredients, including carcinogens. Cosmetic products associated with carcinogenic constituents include hair dyes and, in the past, hair sprays. Gaps in the basic law that controls cosmetics safety-the Federal Food, Drug and Cosmetic Act (FFDCA) are in large part responsible for the Food and Drug Administration (FDA) failing to act on behalf of consumers who use cosmetics.
Regulatory Toxicology and Pharmacology | Year: 2014
Convincing evidence suggests that high-surface-activity nano-materials, such as MWCNT, exert two modes of action (MoA), in which one appears to be related to surface activity/area and occurs concurrent with deposition, and the other is related to cumulative lung burden. Pulmonary inflammation induced by the latter mode appears to be dependent on cumulative volumetric lung burden and on whether the accumulated particle displacement volume within the pool of alveolar macrophages is above or below the kinetic lung overload threshold. However, the relative importance and effect of each MoA are still controversial. In addition, the test protocol variables, which may predetermine the leading MoA, have not yet received increased attention. This study compares the respective outcome of previously published repeated-exposure inhalation studies with MWCNT (Nanocyl and Baytube) in rats. Modeling procedures were performed to compare post hoc the equivalence of empirical and modeled outcomes, including critical protocol variables. This comparison provided compelling evidence that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study designs may not always be appropriate to unequivocally dissociate the surface area/activity-related acute adversity from the cumulative retention volume-related adversity. Thus, in the absence of adequately designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. In summary, this analysis of existing data supports the conclusion that both the deposition and retention-related effects need to be judiciously dissociated to better understand the MoA of heightened concern. This exercise supports the conclusion that hypothesis-based computational study design delivers the highest degree of scientifically important information and may further reduce the number of experimental animals in repeated-exposure inhalation studies with low-toxicity, biopersistent, poorly soluble granular particles. © 2014 Elsevier Inc.
PubMed | Toxicology
Type: | Journal: Neuropharmacology | Year: 2016
Drug users often combine benzodiazepines with psychostimulants, such as methamphetamine. However, very little research has been conducted on this type of polydrug use, particularly in female subjects. The present study was therefore designed to examine the effects of two benzodiazepines, alprazolam and oxazepam, on the discriminative stimulus effects of methamphetamine and cocaine in both male and female rats. Rats were trained to discriminate methamphetamine (1.0mg/kg, ip) or cocaine (10mg/kg, ip) from saline using a two-lever operant, food-reinforced, drug discrimination design. Pretreatment with oxazepam (5, 10 and 20mg/kg, ip) significantly attenuated methamphetamine discrimination in both male and female rats. In contrast, however, the high dose of alprazolam (4mg/kg, ip) actually augmented the subjective effects of lower doses of methamphetamine (0.125 and 0.25mg/kg, ip). Oxazepam produced similar effects on the subjective effects of cocaine as with methamphetamine, significantly reducing cocaine discrimination in both male and female rats. However, neither the high nor low dose of alprazolam (2 and 4mg/kg, ip) produced any apparent effect on cocaine discrimination. Finally, while similar results were observed in both male and female rats across these experiments, methamphetamine and cocaine discrimination were more sensitive to oxazepam in female subjects. The results of these experiments suggest that alprazolam and oxazepam can differentially affect the subjective effects of methamphetamine and cocaine. These results also demonstrate that alprazolam can differentially affect the discriminative stimulus effects of methamphetamine and cocaine.