Method of measuring effects of study procedures in single and pair housed New Zealand White rabbits (Oryctolagus cuniculus).

Social housing of laboratory rabbits is encouraged and thought to improve animal welfare due to the social nature of this species. However, there is limited published information comparing the physiologic and cardiovascular (CV) effects of paired and single housed adult female rabbits in commonly used laboratory caging. This study describes measurement of heart rate, systolic blood pressure, activity level, body temperature and pairing methods in four female New Zealand White rabbits that were previously implanted with M10 cardiovascular telemetry devices. Data was collected in single housed rabbits having no history of social housing while they were undisturbed in the home cage, during restraint, intramuscular injections and intravenous blood collection. The same animals were then placed in compatible pairs and housed in conventional Allentown caging. As expected, we found increased activity in paired rabbits but no significant differences in body temperatures, and CV parameters in single and paired rabbits undergoing the same procedures. These data suggest that paired rabbits can be used for safety pharmacology studies with minimal impact to data, while supporting improved animal welfare.

Zika Virus: A Review of Management Considerations and Controversies at Six Months.

Zika virus continues to pose a significant global health threat. While the outbreak pattern may seemingly mirror those of other arboviruses, unique transmission characteristics and clinical outcomes warrant a different approach to traditional public health practices. Sexual transmission and virus-associated fetal and nonfetal neurologic disorders specifically challenge conventional methods of disease protection and prevention with regard to vector control, disease surveillance, and health risk communication. The protocols for outbreak and case limitation led by the World Health Organization (in accordance with Public Health Emergency of International Concern declaration) may be augmented by localized risk categorization and assignment for Zika and future emergent outbreaks. There is currently a great deal of "behind the scenes" discussion about modifications to the formal process described in the International Health Regulations. A scalable, adaptable, and flexible process is needed that can be customized to a specific threat. (Disaster Med Public Health Preparedness. 2017;11:279-284).

Comparison of ketamine-xylazine and ketamine-dexmedetomidine anesthesia and intraperitoneal tolerance in rats.

We compared ketamine-xylazine (K, 100 mg/kg; X, 10 mg/kg) and ketamine-dexmedetomidine (K, 75 mg/kg; D, 1.0 mg/kg) for their ability to produce anesthesia, their tissue tolerance, and the reversibility of their effects by atipamezole (1.0 mg/kg) after intraperitoneal administration to Wistar Han rats. Both anesthetic combinations led to a comparable level of anesthesia over a 30-min period. However, the administration of KD led to a 20% decrease in heart rate, 33% decrease in respiratory rate, and a 20% decrease in peripheral oxygen saturation from baseline levels. Intraperitoneal administration of saline and both anesthetic combinations was associated with mild transient increases in serum ALT and AST concentrations in the absence of histomorphologic findings in liver. Muscle and tissue necrosis at the intraperitoneal injection sites correlated with increases in serum creatine kinase concentrations in rats given KD or KX; these increases were more severe in the KX group than the KD group. Compared with KX, intraperitoneal administration of KD offered better local tolerance and anesthesia of similar quality and depth.

Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.

The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.

Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma.