US FDA 505(b)(2) NDA clinical, CMC and regulatory strategy concepts to expedite drug development.

The 505(b)(2) NDA pathway can reduce drug development costs and accelerate the time to market by leveraging existing public data using clinical bridging and regulatory strategies. Whether or not a drug qualifies for the 505(b)(2) pathway depends on the active ingredient, drug formulation, clinical indication and other factors. Clinical programs can be streamlined and accelerated, and confer unique marketing benefits, such as exclusivity, depending on the regulatory strategy and product.

Whole-body inhalation exposure to 2-ethyltoluene for two weeks produced nasal lesions in rats and mice.

Objective: Ethyltoluenes are isolated during crude oil refinement for use in gasoline and commercial products and are ubiquitous in the environment. However, minimal toxicity data are available. Previously, we identified 2-ethyltoluene (2-ET) as the most potent isomer via nose-only inhalation exposure in rodents.

Oral deoxynivalenol toxicity in Harlan Sprague Dawley (Hsd:Sprague Dawley® SD®) rat dams and their offspring.

There is widespread human exposure to deoxynivalenol (DON), a fungal mycotoxin found globally in many grain-based foods and animal feed. Acute exposures to high levels of DON are associated with gastrointestinal effects and emesis in humans and some animals, but the effects of low-dose exposures throughout the lifetime, a more likely exposure scenario in humans, are understudied. Therefore, this study was designed to identify doses of DON that could be used to evaluate long-term toxicity following perinatal exposure.

Tolerability and age-dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats.

Hydroxyurea (HU) is a valuable therapy for individuals with sickle cell anemia. With increased use of HU in children and throughout their lives, it is important to understand the potential effects of HU therapy on their development and fertility. Thus, studies were conducted to identify appropriate doses to examine long-term effects of prenatal and early postnatal HU exposure and to understand kinetics of HU at various life stages.

Immunotoxicity studies of trans-resveratrol in male BCF/N mice.

Resveratrol is a naturally occurring polyphenol that is being investigated to treat and prevent various diseases, both experimentally and in the clinic. Despite increased use and interest in resveratrol due to its immunomodulatory properties, there is a lack of studies evaluating potential toxicities, particularly immunotoxicity, associated with resveratrol use. A previous 2-week study found decreasing thymus weight in male BCF/N mice with increasing exposure to trans-resveratrol.

Development of an Analytical Method for Quantitation of Deoxynivalenol by UPLC-MS-MS: A Preliminary Assessment of Gestational and Lactational Transfer in Rats.

Deoxynivalenol (DON) is the most widely distributed trichothecene mycotoxin in grain-based foods and animal feed. Exposure to DON is widespread as it has been detected in food sources from around the world. The objective of this work was to develop a method to quantitate DON in biological matrices and apply it in a preliminary assessment of gestational and lactational transfer of DON following exposure of pregnant rats.

Exposure to inorganic arsenic and its methylated metabolites alters metabolomics profiles in INS-1 832/13 insulinoma cells and isolated pancreatic islets.

Inorganic arsenic (iAs) is an environmental diabetogen, but mechanisms underlying its diabetogenic effects are poorly understood. Exposures to arsenite (iAs) and its methylated metabolites, methylarsonite (MAs) and dimethylarsinite (DMAs), have been shown to inhibit glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated pancreatic islets. GSIS is regulated by complex mechanisms.

Evaluating Sufficient Similarity of Botanical Dietary Supplements: Combining Chemical and In Vitro Biological Data.

Botanical dietary supplements are complex mixtures with numerous potential sources of variation along the supply chain from raw plant material to the market. Approaches for determining sufficient similarity (ie, complex mixture read-across) may be required to extrapolate efficacy or safety data from a tested sample to other products containing the botanical ingredient(s) of interest. In this work, screening-level approaches for generating both chemical and biological-response profiles were used to evaluate the similarity of black cohosh (Actaea racemosa) and Echinacea purpurea samples to well-characterized National Toxicology Program (NTP) test articles.

Arsenite and its trivalent methylated metabolites inhibit glucose-stimulated calcium influx and insulin secretion in murine pancreatic islets.

Chronic exposure to inorganic arsenic (iAs), a common drinking water and food contaminant, has been associated with an increased risk of type 2 diabetes in population studies worldwide. Several mechanisms underlying the diabetogenic effects of iAs have been proposed through laboratory investigations. We have previously shown that exposure to arsenite (iAs(III)) or its methylated trivalent metabolites, methylarsonite (MAs(III)) and dimethylarsinite (DMAs(III)), inhibits glucose-stimulated insulin secretion (GSIS) in pancreatic islets, without significant effects on insulin expression or insulin content.

Metabolic Phenotype of Wild-Type and -Knockout C57BL/6J Mice Exposed to Inorganic Arsenic: The Role of Dietary Fat and Folate Intake.

Background: Inorganic arsenic (iAs) is a diabetogen. Interindividual differences in iAs metabolism have been linked to susceptibility to diabetes in iAs-exposed populations. Dietary folate intake has been shown to influence iAs metabolism, but to our knowledge its role in iAs-associated diabetes has not been studied.

Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner.

Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied.

Knockout of arsenic (+3 oxidation state) methyltransferase is associated with adverse metabolic phenotype in mice: the role of sex and arsenic exposure.

Susceptibility to toxic effects of inorganic arsenic (iAs) depends, in part, on efficiency of iAs methylation by arsenic (+3 oxidation state) methyltransferase (AS3MT). As3mt-knockout (KO) mice that cannot efficiently methylate iAs represent an ideal model to study the association between iAs metabolism and adverse effects of iAs exposure, including effects on metabolic phenotype. The present study compared measures of glucose metabolism, insulin resistance and obesity in male and female wild-type (WT) and As3mt-KO mice during a 24-week exposure to iAs in drinking water (0.

Knockout of arsenic (+3 oxidation state) methyltransferase results in sex-dependent changes in phosphatidylcholine metabolism in mice.

Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that As3mt knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine.

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure.

Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure.