This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.
Ethyl glucuronide (EtG) is a direct ethanol biomarker and U.S. Department of Health and Human Services has advised that specificity studies at low EtG levels are needed for distinction of ethanol consumption and incidental exposure. The authors report urinary EtG excretion with ethanol abstinence, dermal exposure and oral consumption. EtG concentration by sensitive liquid chromatography-tandem mass spectrometry measurement in 39 urine specimens from adult alcohol abstainers (< 10-62 microg/L) and in urine from 13 children (< 10-80 microg/L) indicates either unrecognized ethanol exposure or endogenous ethanol metabolism. With repetitive daily dermal exposure to hand sanitizer (60% ethanol) by 9 adults, EtG concentration ranged from < 10 to 114 microg/L in 88 first-morning void specimens. EtG excretion following a 24 g ethanol drink by 4 adults revealed maximum urine EtG concentration (12,200-83,200 microg/L) at 3 to 8 h postdose and an EtG detection window up to 25-39 h, compared to an ethanol window of only 2 to 4 h. Oral ethanol use also showed an increase in the percent (molar equivalent) ethanol excreted as EtG with increasing oral ethanol doses. Human excretion studies show 1. EtG detectable at low concentration (< 100 microg/L) when ethanol use or exposures is not evident, 2. EtG concentration less than 120 microg/L in first morning specimens from adults with repeated dermal exposure to ethanol, 3. EtG levels maximally elevated within 3-8 h and above baseline for up to 39 h after a 24 g ethanol drink, and 4. a dose-dependent increase in the percentage of ethanol excreted as EtG with increasing oral ethanol use.
Autism spectrum disorder (ASD) is a type of neurodevelopmental disorder that has been diagnosed in an increasing number of children around the world. Existing data suggest that early diagnosis and intervention can improve ASD outcomes. However, the causes of ASD remain complex and unclear, and there are currently no clinical biomarkers for autism spectrum disorder. More mechanisms and biomarkers of autism have been found with the development of advanced technology such as mass spectrometry. Many recent studies have found a link between ASD and elevated oxidative stress, which may play a role in its development. ASD is caused by oxidative stress in several ways, including protein post-translational changes (e.g., carbonylation), abnormal metabolism (e.g., lipid peroxidation), and toxic buildup [e.g., reactive oxygen species (ROS)]. To detect elevated oxidative stress in ASD, various biomarkers have been developed and employed. This article summarizes recent studies about the mechanisms and biomarkers of oxidative stress. Potential biomarkers identified in this study could be used for early diagnosis and evaluation of ASD intervention, as well as to inform and target ASD pharmacological or nutritional treatment interventions.
Background: Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces signi cant challenges due to the existence of heterogeneity.Methods: In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out.Results: The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, PBMCs, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focus on several common and previously reported mechanisms of ASD.Limitations: The number of samples carrying risk genes in omics research is limited. In further research, a large sample size is required. A group of children who have been diagnosed with ASD but have not been detected to carry risk genes should also be included. Conclusion:The biomarkers for ASD diagnosis could be found by taking DEPs and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.
Acrolein (Acr), a highly reactive unsaturated aldehyde, can cause various lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We have found that Acr can damage not only genomic DNA but also DNA repair proteins causing repair dysfunction and enhancing cells’ mutational susceptibility. While these effects may account for Acr lung carcinogenicity, the mechanisms by which Acr induces lung diseases other than cancer are unclear. In this study, we found that Acr induces damages in mitochondrial DNA (mtDNA), inhibits mitochondrial bioenergetics, and alters mtDNA copy number in human lung epithelial cells and fibroblasts. Furthermore, Acr induces mitochondrial fission which is followed by autophagy/ mitophagy and Acr-induced DNA damages can trigger apoptosis. However, the autophagy/ mitophagy process does not change the level of Acr-induced mtDNA damages and apoptosis. We propose that Acr-induced mtDNA damages trigger loss of mtDNA via mitochondrial fission and mitophagy. These processes and mitochondria dysfunction induced by Acr are causes that lead to lung diseases.
Abstract. The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/ pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses,~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally,~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.
Arsenic (As) is one of the most important toxic elements in the natural environment. Currently, although the assessment of the potential health risks of chronic arsenic poisoning has received great attention, the research on the effects of arsenic on the brain is still limited. It has been reported that dictyophora polysaccharide (DIP), a common bioactive natural compound found in dietary plants, could reduce arsenic toxicity. Following behavioral research, comparative proteomics was performed to explore the molecular mechanism of arsenic toxicity to the hippocampi of SD (Sprague Dawley) rats and the protective effect of DIP. The results showed that exposure to arsenic impaired the spatial learning and memory ability of SD rats, while DIP treatment improved both the arsenic-exposed rats. Proteomic analysis showed that arsenic exposure dysregulated the expression of energy metabolism, apoptosis, synapse, neuron, and mitochondria related proteins in the hippocampi of arsenic-exposed rats. However, DIP treatment reversed or restored the expression levels of these proteins, thereby improving the spatial learning and memory ability of arsenic-exposed rats. This study is the first to use high-throughput proteomics to reveal the mechanism of arsenic neurotoxicity in rats as well as the protective mechanism of DIP against arsenic neurotoxicity.
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