Combined Cardiopulmonary Assessments Using Impedance and Digital Implants in Conscious Freely Moving Cynomolgus Monkeys, Beagle Dogs, and Göttingen Minipigs: Pharmacological Characterization and Social Housing Effects.

Respiratory monitoring, using impedance with implanted telemetry in socially housed animals, was not possible until the recent development of digital signal transmission. The objective of this study was to evaluate digital telemetry monitoring of cardiopulmonary parameters (respiratory rate, tidal volume, minute volume, electrocardiography (DII), systemic arterial blood pressure, physical activity, and body temperature) in conscious, single-housed, non-rodent species commonly used in toxicology studies following administration of positive/negative controls (saline, dexmedetomidine, morphine, amphetamine, and doxapram), and also, the effects of various social housing arrangements in untreated female and/or male cynomolgus monkeys, Beagle dogs, and Göttingen minipigs (n = 4 per species). Aggressions were observed in socially housed male minipigs, however, which prevented pair-housed assessments in this species. All tested pharmacological agents significantly altered more than one organ system, highlighting important inter-organ dependencies when analyzing functional endpoints. Stress-related physiological changes were observed with single-housing or pair-housing with a new cage mate in cynomolgus monkeys and Beagle dogs, suggesting that stable social structures are preferable to limit variability, especially around dosing. Concomitant monitoring of cardiovascular and respiratory parameters from the same animals may help reduce the number of animals (3 Rs) needed to fulfill the S7A guidelines and allows for identification of organ system functional correlations. Globally, the data support the use of social housing in non-rodents for safety pharmacology multi-organ system (heart and lungs) monitoring investigations.

Respiratory mechanics: comparison of Beagle dogs, Göttingen minipigs and Cynomolgus monkeys.

INTRODUCTION: When the no observed adverse effect level (NOAEL) is determined by respiratory safety pharmacology, follow-up studies are warranted and may include airway resistance and compliance. Respiratory mechanics in commonly used large animal species (Beagle dogs, Cynomolgus monkeys, and Göttingen minipigs) were compared. METHODS: Eighteen animals were used (3/sex/species) in an anesthetized model (propofol infusion) with pancuronium as a neuromuscular blocker. Parameters of respiratory mechanics were evaluated at baseline and at peak drug effect. Resistance (Rrs) and elastance (Ers) were measured by applying a single frequency forced oscillation (0.5 Hz) to the subject's airway opening and fitting the flow, volume and pressure data to the single compartment model of the lung. Increasing doses of intravenous (IV) methacholine were administered in all three species, as well as doubling aerosolized concentrations of the same bronchoconstrictor agent before and after inhaled albuterol. RESULTS: The slope of the IV methacholine dose-response curve for Rrs was similar in dogs and monkeys and both species differed from minipigs, which showed greater reactivity. At the highest IV dose tested, minipigs also reached higher levels of bronchoconstriction than the other two species. They were followed, in decreasing order, by dogs and monkeys. Albuterol induced a significant decrease in the slope of the dose-response curve only in dogs and monkeys. DISCUSSION: Scientific literature is available on respiratory mechanics in monkeys and dogs but not in minipigs. Our results suggest that minipigs were more reactive than dogs and monkeys to IV methacholine while less sensitive to inhaled albuterol.