Objective—To investigate physiologic effects of electroacupuncture (EA) combined with xylazine administration in goats.
Animals—48 healthy crossbred goats.
Procedures—Goats were randomly allotted to 8 groups of 3 (nonpregnant and nonlactating) female goats and 3 male goats each. The 8 treatment groups were as follows: 1 EA group, 3 xylazine (0.1, 0.2, and 0.4 mg/kg, IM) groups, 3 EA plus xylazine (0.1, 0.2, and 0.4 mg/kg, IM) groups, and 1 control group. Electroacupuncture was performed for 90 minutes. Xylazine was administered 20 minutes after EA was performed. Pain threshold, heart rate, mean arterial pressure (MAP), respiration rate, and rectal temperature were observed at 0, 5, 25, 45, 65, and 85 minutes after xylazine administration.
Results—Xylazine administered at 0.4 mg/kg increased the pain threshold and reduced MAP. Xylazine administered at 0.1, 0.2, or 0.4 mg/kg reduced heart rate, respiration rate, and temperature. Electroacupuncture increased the pain threshold but had no effect on heart rate, MAP, respiratory rate, or rectal temperature. Pain threshold in goats that underwent EA plus xylazine administration was higher than in goats that received EA or xylazine alone. Electroacupuncture combined with xylazine at 0.1 mg/kg did not affect heart rate, MAP, respiratory rate, or rectal temperature. Pain threshold in goats that underwent EA plus xylazine administration at 0.1 mg/kg was higher than in goats given xylazine at 0.4 mg/kg alone.
Conclusions and Clinical Relevance—Electroacupuncture combined with xylazine, even at 0.1 mg/kg, provided analgesia without significantly affecting cardiorespiratory parameters or rectal temperature in goats.
Objective—To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1Δ).
Animals—8 ABCB1 knock-in and knock-out transgenic mice expressing the ABCB1-1Δ gene and 8 control mice expressing the wild-type canine ABCB1 gene (ABCB1-WT).
Procedures—Groups including 2 ABCB1-1Δ mutant mice and 2 ABCB1-WT mice were administered the P-gp substrates ivermectin (10 mg/kg, SC), doramectin (10 mg/kg, SC), moxidectin (10 mg/kg, PO), or digoxin (1.53 mg/kg, SC). A toxicogenomic approach based on DNA microarrays was used to examine whole-genome expression changes in mice administered P-gp substrates.
Results—Compared with control ABCB1-WT mice, ABCB1-1Δ mutant mice developed neurotoxic signs including ataxia, lethargy, and tremors similar to those reported for dogs with the ABCB1-1Δ mutation. Microarray analysis revealed that gene expression was altered in ABCB1-1Δ mutant mice, compared with findings for ABCB1-WT mice, following administration of the same P-gp substrates. Gene pathway analysis revealed that genes with a ≥ 2-fold gene expression change were associated with behavior and nervous system development and function. Moreover, 34 genes were altered in the ABCB1-1Δ mutant mice in all 4 drug treatment groups. These genes were also associated with behavior, which was identified as the top-ranked gene network.
Conclusions and Clinical Relevance—These study data have facilitated understanding of the molecular mechanisms of neurotoxicosis in ABCB1-1Δ mutant mice following exposure to various P-gp substrates. Some genes appear to be potential biomarkers of P-gp substrate neurotoxicity that might be used to predict the safety of those drugs in dogs with the ABCB1-1Δ mutation.