A Commentary on Fasting of Nonclinical Research Animals.

This commentary discusses the implementation of fasting in nonclinical animal experimental subjects. The short-term removal of food from cages of experimental animals is in all respects innocuous. The term "stress" is ill-defined and the statutes and regulations governing animal research laboratories that exert their authority in the performance of their operations do so without substantive grounds to base compliance.

The Canadian Longitudinal Study on Aging: A Vehicle for Research on Aging in Older Veterans.

Introduction: Research on the health of older Veterans in Canada is an emerging area. Few population-based studies in Canada have included older Veterans as a specific group of interest. This paper describes a cohort of self-identified Veterans within the Canadian Longitudinal Study on Aging (CLSA).

REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats.

REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted.

Distortion Product Otoacoustic Emission Test is Not the Test to Use in Nonclinical Safety Assessment.

Ototoxicity and ocular toxicity screening are but two examples of specialty product lines that are often employed as Tier II or III nonclinical safety/hazard screening assessments. Compared to the regulatory guidelines that govern over standard toxicology or neurotoxicology programs, there is a paucity of regulatory strategies to address these specialized product lines. With respect to ototoxicity testing, we argue for the inclusion of the "least burdensome principles" adopted by the US FDA in providing the most pragmatic, efficient, and directed identification of potential harm to auditory function in the nonclinical safety arena.

De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.

Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant.

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys.

Study design criteria for regulatory-based drug control action: Drug discrimination.

This "methods paper" focusses on one specific and limited aspect of drug safety evaluations required for all new drug entities that affect the central nervous system - the drug discrimination (DD) assay. We focus on three critical factors involved in experimental design and protocol development for the conduct of DD studies for abuse liability risk assessment that comply with the Good Laboratory Practice Guidelines (GLPs). The selection of 1) the reference drug(s) choice, 2) training dose selection, and 3) the selected route-of-administration will determine the applicability of the data to meet the regulatory expectations of the 8-factors determinative of schedule control recommendations.

ACT1 Is Required for Murine IL-23-Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity.

Psoriasis is a debilitating skin disease characterized by epidermal thickening, abnormal keratinocyte differentiation, and proinflammatory immune cell infiltrate into the affected skin. IL-17A plays a critical role in the etiology of psoriasis. ACT1, an intracellular adaptor protein and a putative ubiquitin E3 ligase, is essential for signal transduction downstream of the IL-17A receptor.

Waterborne outbreaks: a public health concern for rural municipalities with unchlorinated drinking water distribution systems.

Objectives: The objective of this study is to describe an important waterborne outbreak of gastrointestinal illness observed in a rural municipality of Quebec.

Methods: A population-based retrospective cohort study was conducted to identify risk factors associated with acute gastroenteritis. Indirect surveillance data were used to estimate the extent and the resolution of the epidemic.

IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases.

Foxp3 regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity.

CNS Safety Screening Under ICH S7A Guidelines Requires Observations of Multiple Behavioral Units to Assess Motor Function.

In the adoption of behavior as a critical end point in safety pharmacology and neurotoxicity screening, federal regulatory agencies have shifted the predominating scientific perspective from pharmacology back to the experimental analysis of behavior (psychology). Nowhere is this more evident than in tier I safety assessment of the central nervous system (CNS). The CNS and peripheral nervous system have multiple behavioral units of general activity.

Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of RORt.

Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) t and its efficacy in preclinical models of psoriasis and arthritis.

Predicting the Need for a Tier II Ototoxicity Study From Early Renal Function Data.

History has established that many drugs, such as the antibiotics, chemotherapies, and loop diuretics, are capable of inducing both nephrotoxicity and ototoxicity. The exact mechanisms by which cellular damage occurs remain to be fully elucidated. Monitoring the indices of renal function conducted in the Food and Drug Administration's prescribed set of early investigational new drug (IND)-enabling studies may be the first signs of ototoxicity properties of the new drug candidate.

NOEL and NOAEL: A retrospective analysis of mention in a sample of recently conducted safety pharmacology studies.

Introduction: The concept of characterizing adversity in relation to administered test article dose and/or exposure within toxicology studies has long been considered a normal aspect of the drug safety evaluation enterprise. The typical way this is done in drug safety investigations is by examining study data, often with focus on clinical signs, clinical pathology and histopathology, to determine a No-Observable-Effect-Level (NOEL) and/or a No-Observable-Adverse-Effect-Level (NOAEL). Once established, these, with other information, may be used to identify a safe starting dose in human clinical trials.

Extended recording of LMA in rats: Effects of IV catheters, "comfort jackets" and chamber lids on arterial blood gas parameters.

The standard infrared photobeam locomotor activity system has been used extensively in neurobiology and neuropharmacology to study the functional impact of direct manipulations of the nervous system. There is interest in using the activity monitors to assess the early stages of drug withdrawal in rodents. In a standard twice-daily dosing strategy animals would be dosed at 6:00 am and 5:00 pm for 15 to 30 days.

Characterization of psoriasiform dermatitis induced by systemic injection of interleukin-23 minicircles in mice.

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.

Monocytes/Macrophages play a pathogenic role in IL-23 mediated psoriasis-like skin inflammation.

Psoriasis is an immune-mediated inflammatory skin disease that affects millions worldwide. Studying immune cells involved in psoriasis pathogenesis is essential to identify effective and safe therapeutics for the disease. Using human psoriasis skin, activated macrophages were observed in both lesional and non-lesional skin, but were elevated in lesional skin.

FOB vs modified Irwin: What are we doing?

There is a general sentiment in the nonclinical safety assessment literature and the proponents of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), that the "Modified Irwin" and the Functional Observation Battery are distinct and unique assays for the nonclinical assessment of the central nervous system (CNS). We identify and defend the position that the Irwin screen was developed as an FOB and both terms refer to a single, unitary functional assay. In giving credit to one prominent contributor to any one significant discipline of science for a specific assay, orientation, or theory may have an exclusionary influence on the merits of other prominent contributors within the same research arena.

Establishing performance characteristics for positive control article selection in drug self-administration studies.

The selection of a controlled substance (CS) for use as the positive control article in a nonclinical drug abuse liability (DAL) assessment study should be contemplated carefully and with full understanding of the stated intent of the study design. Any CS that can maintain day-to-day stable baseline responding of voluntary intravenous intakes in animals may be selected under the current guidelines. Schedule I - IV CNS stimulants, depressants, and sedative/hypnotics can serve as maintenance drugs in these protocols, but not all of these compounds will provide comparatively efficient, robust, and stable daily intakes.

Relative equivalence of CNS safety (FOB) assessment outcomes in male and female Wistar-Han and Sprague-Dawley rats.

In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain.

In further defense of nonclinical abuse liability testing of biologics.

Risk assessment is not a choice. Drug Abuse Liability (DAL) is mandated under international and national drug control statutes for all drugs targeting the CNS. Once administered to humans many biologics may have long-lived or permanent physiological effects that make DAL testing arduous.

"Not Everything That Shakes Is a Seizure": Making the Determination of Test Article-Induced Convulsions in Toxicology Studies.

Spontaneous unexpected events occasionally develop during the course of rodent preclinical toxicology studies. The presentation of serious adverse events on animal studies may require notification of these events to the Food and Drug Administration if the events are most likely the direct result of test article administration. Classical conditioning of emotional responses may occur over the course of a repeat-dose study and clinical observation calls of "convulsions" are reported to the study director and/or staff veterinarians.