A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.
This verified that the Hanford miniature swine is the preferable strain for phototoxic effects. In contrast, UVR exposure of the Yucatan pig skin produced tanning rather than erythema, confirming that the Yucatan is the more appropriate strain for studying the melanization response. Thus, Hanford and Yucatan miniature swine have cutaneous photobiological responses that reflect their respective strain differences.
Aim: Oral and intravenous pharmacokinetic (PK) studies were conducted in four different minipig strains: Sinclair, Yucatan, Hanford and Göttingen after administration of metformin or R,S-verapamil (R,S-VER). Results: The results indicated that the PK of metformin was similar between all minipig strains, except for the Göttingen which had higher plasma clearance. The plasma clearance of both (+)-(R)- and (−)-(S)-VER was significantly lower in Sinclair compared with the clearance in other strains. The (+)-(R)-NOR to R,S-VER ratio was significantly higher in the Sinclair. There was a preferential conversion of R,S-VER to (+)-(R)-NOR over (−)-(S)-NOR in all minipig strains. Conclusion: This work highlights the importance of considering the impact of metabolic and dispositional differences in minipig strains when conducting PK studies.
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