Pharmacokinetics of Extended-release Buprenorphine in Mongolian Gerbils (Meriones unguiculatus).

Both the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act and Regulations require animals in research to receive adequate analgesia unless an exception can be scientifically justified and IACUC approved. Extended- release buprenorphine (BUP-XR) is a pharmaceutical-grade formulation that is FDA-indexed for use in mice and rats. However, this new formulation has not been evaluated in adult Mongolian gerbils (Meriones unguiculatus). Our goal was to determine whether the extrapolated dose (1 mg/kg SC) would achieve plasma buprenorphine concentrations above the murine therapeutic threshold (> 1.0 ng/mL) in male and female gerbils. We hypothesized that BUP-XR administered at 1 mg/kg would achieve the murine therapeutic threshold in both male and female gerbils until at least 48 h after injection. Gerbils received one injection of BUP-XR (1 mg/kg SC) and underwent 4 serial blood collections (0.5, 1, 2, and 4, or 0.5, 24, 48, and 72 h after injection). The average plasma buprenorphine concentrations were above 1 ng/mL within 30 min of administration for both males and females. Plasma buprenorphine concentrations remained above 1.0 ng/mL for 48 h after administration. In males, plasma buprenorphine concentrations were significantly higher at 1 h after injection as compared with females; no other significant differences were observed between sexes. Mild to moderate injection-site granulomas were observed in five of nine gerbils, presumably due to the lipid matrix of the BUP-XR formulation. Our findings demonstrate that a single BUP-XR dose (1 mg/kg SC) achieves plasma buprenorphine levels that remain above the murine therapeutic threshold of 1.0 ng/mL for up to 48 h in both sexes.

Confirmation of Pathogen 'Burnout' in Mouse Colonies with Previous Evidence of Infection with Parvovirus and Rotavirus.

Pathogen monitoring and colony health management are critical components of any rodent research program. From an operational perspective, rodent facilities are protected from unwanted infectious agents by facility-specific bioexclusion criteria, sanitation of the physical environment, and personal protective equipment. Another important preventative measure is the use of room health levels to provide traffic patterns for animal care and research staff as they move between rooms of differing health status. For mice, our institution uses a tiered room level system with 6 defined categories, ranging from level 1 (strictest entry criteria) to 6 (least stringent entry criteria). Level 6 is defined as rooms with mice that have tested positive for mouse parvovirus (MPV) or mouse rotavirus (MRV) or both on sentinel serology at any point in time in the past and no decontamination. Because many of our mouse rooms had historically been positive for MPV and/or MRV and because of the high financial and logistic challenges of using repeated test-and-cull for elimination, we had tolerated the potential presence of MPV and MRV and had developed management practices that would promote 'burnout' (that is, elimination of infectious agents due to absence of susceptible hosts) of these pathogens. Analysis of sentinel data showed that we had 28 rooms in 4 facilities for which excluded pathogens had not been identified in 3 y or more. We therefore developed a hybrid testing strategy involving both PCR analysis and serology and implemented it in sentinels and in select colony mice to determine whether the rooms had undergone successful burnout and were free of MPV and MRV. All test results obtained during the assessment were negative for both viruses, and the rooms were subsequently upgraded to level 5 (free from excluded pathogens and allowing two-way movement in and out of housing room). All upgraded rooms have remained negative on subsequent quarterly routine sentinel serology for over 3 y. Our testing strategy for confirming pathogen burnout may be a useful and cost-efficient model for other academic rodent research programs that face a similar situation.

Hepatic and Whole-Body Insulin Metabolism during Proestrus and Estrus in Mongrel Dogs.

Insulin resistance occurs during various stages of the estrus cycle in dogs. To quantify the effects of proestrus-estrus (PE) and determine whether PE affects liver insulin sensitivity, 11 female mongrel dogs were implanted with sampling and intraportal infusion catheters. Five of the dogs (PE group) entered proestrus after surgery; those remaining in anestrus were controls. The dogs were fasted overnight, [3-(3)H]glucose and somatostatin were infused through peripheral veins, and glucagon was infused intraportally. Insulin was infused intraportally, with the rate adjusted to maintain arterial plasma glucose at basal levels (PE, 294±25 µU/kg/min; control, 223±21 µU/kg/min). Subsequently the insulin infusion rate was increased by 0.2 mU/kg/min for 120 min (P1) and then to 1.5 mU/kg/min for the last 120 min (P2); glucose was infused peripherally as needed to maintain euglycemia. Insulin concentrations did not differ between groups at any time; they increased 3 µU/mL over baseline during P1 and to 3 times baseline during P2. The glucose infusion rate in PE dogs during P2 was 63% of that in control dogs. Net hepatic glucose output and the endogenous glucose production rate declined 40% to 50% from baseline in both groups during P1; during P2, both groups exhibited a low rate of net hepatic glucose uptake with full suppression of endogenous glucose production. The glucose disappearance rate during P1 and P2 was 35% greater in control than PE dogs. Therefore, PE in canines is associated with loss of nonhepatic (primarily muscle) but not hepatic insulin sensitivity.