Toxicology and applied pharmacology
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Toxicol. Appl. Pharmacol. · Sep 2018
ReviewLipid profiling as an effective approach for identifying biomarkers/adverse events associated with pediatric anesthesia.
Adverse effects related to central nervous system (CNS) function in pediatric populations may, at times, be difficult, if not impossible to evaluate. Prolonged anesthetic exposure affects brain excitability and anesthesia during the most sensitive developmental stages and has been associated with mitochondrial dysfunction, aberrant lipid metabolism and synaptogenesis, subsequent neuronal damage, as well as long-term behavioral deficits. There has been limited research evaluating whether and how anesthetic agents affect cellular lipids, the most abundant components of the brain other than water. Therefore, this review discusses: (1) whether the observed anesthetic-induced changes in lipid profiles seen in preclinical studies represents early signs of neurotoxicity; (2) the potential mechanisms underlying anesthetic-induced brain injury; and (3) whether lipid biomarker(s) identified in preclinical studies can serve as markers for the early clinical detection of anesthetic-induced neurotoxicity.
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Toxicol. Appl. Pharmacol. · May 2010
ReviewThe discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity.
Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. ⋯ For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other "omics" technologies can provide added selectivity and sensitivity in preclinical drug safety testing.
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Toxicol. Appl. Pharmacol. · Nov 2008
ReviewThermoregulatory responses to environmental toxicants: the interaction of thermal stress and toxicant exposure.
Thermal stress can have a profound impact on the physiological responses that are elicited following environmental toxicant exposure. The efficacy by which toxicants enter the body is directly influenced by thermoregulatory effector responses that are evoked in response to high ambient temperatures. In mammals, the thermoregulatory response to heat stress consists of an increase in skin blood flow and moistening of the skin surface to dissipate core heat to the environment. ⋯ The protective effect of hypothermia is realized by its effects on chemical toxicity as molecular and cellular processes, such as lipid peroxidation and the formation of reactive oxygen species, are minimized at reduced core temperatures. The beneficial effects of fever are unknown under these conditions. Perspective is provided on the applicability of data obtained in rodent models to the human condition.
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Toxicol. Appl. Pharmacol. · May 2008
ReviewFactors affecting toxicity and efficacy of polymeric nanomedicines.
Nanomedicine is the application of nanotechnology to medicine. The purpose of this article is to review common characteristics of polymeric nanomedicines with respect to passive targeting. We consider several biodegradable polymeric nanomedicines that are between 1 and 100 nm in size, and discuss the impact of this technology on efficacy, pharmacokinetics, toxicity and targeting. ⋯ The dissemination of polymeric nanomedicines in vivo depends on the capillary network, which can provide differential access to normal and tumor cells. The accumulation of nanomedicines in the microlymphatics depends upon retention time in the blood and extracellular compartments, as well as the type of capillary endothelium surrounding specific tissues. Finally, the toxicity or efficacy of intact nanomedicines is also dependent upon tissue type, i.e., non-endocrine or endocrine tissue, spleen, or lymphatics, as well as tumor type.
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Toxicol. Appl. Pharmacol. · Apr 2006
ReviewDiabetes and mitochondrial function: role of hyperglycemia and oxidative stress.
Hyperglycemia resulting from uncontrolled glucose regulation is widely recognized as the causal link between diabetes and diabetic complications. Four major molecular mechanisms have been implicated in hyperglycemia-induced tissue damage: activation of protein kinase C (PKC) isoforms via de novo synthesis of the lipid second messenger diacylglycerol (DAG), increased hexosamine pathway flux, increased advanced glycation end product (AGE) formation, and increased polyol pathway flux. Hyperglycemia-induced overproduction of superoxide is the causal link between high glucose and the pathways responsible for hyperglycemic damage. ⋯ This review focuses on a range of mitochondrial factors important in the pathogenesis of diabetes. We review the published literature regarding the direct effects of hyperglycemia on mitochondrial function and suggest the possibility of regulation of mitochondrial function at a transcriptional level in response to hyperglycemia. The main goal of this review is to include a fresh consideration of pathways involved in hyperglycemia-induced diabetic complications.