Pharmacokinetics and Tolerability of the Novel Non-immunosuppressive Fingolimod Derivative, OSU-2S, in Dogs and Comparisons with Data in Mice and Rats.

In this study, we characterized the pharmacokinetics of OSU-2S, a fingolimod-derived, non-immunosuppressive phosphatase activator, in mice, rats, and dogs, as well as tolerability and food effects in dogs. Across all species tested, plasma protein binding for OSU-2S was > 99.5%, and metabolic stability and hepatic intrinsic clearance were in the moderate range. OSU-2S did not significantly modulate CYP enzyme activity up until 50 µM, and Caco-2 data suggested low permeability with active efflux at 2 µM. Apparent oral bioavailability in mice was 16% and 69% at 10 and 50 mg/kg, respectively. In rats, bioavailability was 24%, 35%, and 28% at 10, 30, and 100 mg/kg, respectively, while brain/plasma ratio was 36 at 6-h post-dose at 30 mg/kg. In dogs, OSU-2S was well tolerated with oral capsule bioavailability of 27.5%. Plasma OSU-2S exposures increased proportionally over a 2.5-20 mg/kg dose range. After 4 weeks of 3 times weekly, oral administration (20 mg/kg), plasma AUClast (26.1 µM*h), and Cmax (0.899 µM) were nearly 2-fold greater than those after 1 week of dosing, and no food effects were observed. The elimination half-life (29.7 h), clearance (22.9 mL/min/kg), and plasma concentrations of repeated oral doses support a 3-times weekly dosing schedule in dogs. No significant CBC, serum biochemical, or histopathological changes were observed. OSU-2S has favorable oral PK properties similar to fingolimod in rodents and dogs and is well tolerated in healthy animals. This work supports establishing trials of OSU-2S efficacy in dogs with spontaneous tumors to guide its clinical development as a cancer therapeutic for human patients.

Using a Staff Survey to Customize Burnout and Compassion Fatigue Mitigation Recommendations in a Lab Animal Facility.

Working with research animals exposes employees to emotionally demanding work and moral stressors. The emotional impact of animal research is similar to that of working with human patients, and is similarly associated with burnout (BNO) or compassion fatigue (CF), which can lead to psychosomatic symptoms, pervasive states of stress, workplace conflict, and at its most extreme, suicidal ideation. One remedy for such feelings is increasing the satisfaction one feels from performing one's job well, known as compassion satisfaction (Csat). To address these occupational health concerns in an academic research setting, the Ohio State University's Lab Animal Resources (ULAR) study team reviewed existing preventative programing both internal and external to the university. Subsequently, a survey was distributed to all staff members to assess the following factors: employee awareness of free resources already available to them, association between staff demographics and the experience of BNO and/or CF, and the employee's own mitigation recommendations. Respondents were mostly female, in 20 to 49 age range, with 0 to 4 y in the field. Of those responding, 81.6% specified that they had experienced BNO and CF alone, together, or in combination with CSat. Factors statistically associated (P < 0.05) with BNO and CF were age, number of years in the field, and number of animals euthanized per year. A relative risk analysis was also used to identify protective factors. Only the age of respondents appeared to be a protective factor- the 50+ age group had 88.57% (RR = 0.1143) reduction in risk for experiencing BNO and/or CF. Participant suggestions indicated that employees would like improvements to the work environment, more novel work experiences, and more positive feedback from department leadership. The social ecological model, a public health model for program interventions, was used as a framework for the development of recommendations to mitigate BNO and CF while increasing CSat. The recommendations were customized for ULAR employees based on the survey findings.

Performance analysis of exam gloves used for aseptic rodent surgery.

Aseptic technique includes the use of sterile surgical gloves for survival surgeries in rodents to minimize the incidence of infections. Exam gloves are much less expensive than are surgical gloves and may represent a cost-effective, readily available option for use in rodent surgery. This study examined the effectiveness of surface disinfection of exam gloves with 70% isopropyl alcohol or a solution of hydrogen peroxide and peracetic acid (HP-PA) in reducing bacterial contamination. Performance levels for asepsis were met when gloves were negative for bacterial contamination after surface disinfection and sham 'exertion' activity. According to these criteria, 94% of HP-PA-disinfected gloves passed, compared with 47% of alcohol-disinfected gloves. In addition, the effect of autoclaving on the integrity of exam gloves was examined, given that autoclaving is another readily available option for aseptic preparation. Performance criteria for glove integrity after autoclaving consisted of: the ability to don the gloves followed by successful simulation of wound closure and completion of stretch tests without tearing or observable defects. Using this criteria, 98% of autoclaved nitrile exam gloves and 76% of autoclaved latex exam gloves met performance expectations compared with the performance of standard surgical gloves (88% nitrile, 100% latex). The results of this study support the use of HP-PA-disinfected latex and nitrile exam gloves or autoclaved nitrile exam gloves as viable cost-effective alternatives to sterile surgical gloves for rodent surgeries.

Operant task performance and corticosterone concentrations in rats housed directly on bedding and on wire.

The present experiment was designed to investigate the effect of housing conditions on task performance and corticosterone response. Two groups of male F344BNF1 rats were housed on a ventilated rack with ad libitum access to water and a restricted feeding regime. Group 1 was housed in solid-bottom caging with corn cob bedding, whereas group 2 was housed in wire-bottom caging. After learning an operant task, each rat was exposed to acute restraint followed 48 h later by exposure to continuous light. Corticosterone concentrations were determined before and after exposure to each intervention. Contrary to assumptions, housing did not affect task performance. Baseline corticosterone concentrations were similar for the 2 experimental groups, but corticosterone concentrations were significantly higher for the wire-bottom group than the solid-bottom group immediately after the restraint and remained elevated 2 d later. Corticosterone levels decreased in both groups after exposure to continuous light. Overall, the data indicate that subtle but significant differences occur in responses of rats housed on wire-bottom versus solid-bottom caging when the animals are exposed to acute restraint.